Hydrophilic/lipophilic polymeric matrix dosage formulation

ABSTRACT

An oral dosage form comprising a pharmaceutical tablet of one or more layers, one of which carries a biologically active substance; the formulation of said tablet includes different percentages of hydrophilic and lipophilic polymeric materials, and adjuvant substances. The tablets of the present invention show a release rate which is independent from the amounts of active substance present in the tablet.

-Related Applications

This application is a continuation of U.S. Application No. 11/717,502filed on Mar. 12, 2007, which is a continuation of U.S. Application No.10/257,709 filed on Mar. 10, 2003, which is a National Stage entry ofInternational Application No. PCT/GB01/01726 filed on Apr. 12, 2001which claims priority to Italian patent application Nos. M12000 A000852and M12000 A001963 filed on Apr. 14, 2000, and Sept. 7, 2000respectively. The contents of all of these applications are incorporatedby reference in their entireties.

The present invention relates to a dosage formulation or tabletcomprising a mixed matrix of hydrophilic and lipophilic components ableto control the release rate of one or more therapeutically active agentsfrom the formulation/tablet.

Recent years have seen considerable efforts made in the pharmaceuticaltechnology field of research aimed at preparing innovativepharmaceutical forms, meant for the administration of active substances,both in human treatment and the veterinary field. One of the fundamentalaspects of the innovative qualifies of pharmaceutical dosage formsand/or prepared formulation systems is the potential targeting therelease of the drug (or the active substance) to a specific site ofaction and/or of releasing such active substances with an a prioriprogrammable velocity which can be assessed by way of suitable “invitro” tests.

Other sectors are also interested in these technical fields, not justthe human health sector, namely veterinary and agricultural sectors,especially with regard to the controlled release of fertilisers,weedkillers, insecticides and/or specific protection agents for certaincultures.

There are many examples in the pharmaceutical sector which describe thepreparation of pharmaceutical forms capable of releasing the activeprinciple (active substance) with zero kinetics. As is well known toexperts in the field, this means that the active principle carried isgiven up by the pharmaceutical form at a constant velocity through timeand for a programmable time period. In particular, the release of a drugcan be expressed by the following empirical relation:M _(t) /M ₀ =Kt ^(n)the fraction of drug released (M_(t)/M₀) is proportional to a constant Kwhich depends on the diffusion coefficient in the matrix, whereas theconstant n depends on the swelling characteristics and the relaxationvelocity of the polymeric chains on the swelling front. There are manyexamples of such pharmaceutical forms, for example, is quoted in thevolume of S. Dimitriu “Polysaccharides in medical applications” M.Dekker, New York 1996.

There are many examples and pharmaceutical applications that concerndosage forms utilisable for different administration forms namely oral,transdermal, vaginal and ocular. Certainly, given the extreme importanceand the widespread use of oral drug administration, the more numerousand differentiated embodiments are those aimed at releasing the activeprinciple in the gastrointestinal tract, for example, the OROS systemdescribed in U.S. Pat. No. 4,160,020.

Further progress in this field is also provided by the pharmaceuticaloral dosage forms described in U.S. Pat. No. 4,839,177 and U.S. Pat. No.5,422,123 (equivalent to EP-A-0226884 and EP-A-0432607 respectively)which describes the preparation of pharmaceutical forms for oral usecapable of guaranteeing the liberation of an active principle at aconstant release velocity, i.e. according to zero kinetics (n=0 in theabove formula). In particular, these documents describe the preparationof a therapeutic system consisting, in its simplest form, a hydrophilicmatrix containing a drug and suitable excipients, capable of allowingthe release of the active principle at varied rates (i.e. at controlledrates of release).

Constituent components important in causing the slowed release of theactive principle are the hydrophilic polymers, which may be gellable,and are capable of swelling upon contact with water and/or aqueousfluids, forming a gelled layer from which the active principle spreadsaccording to Fickian type kinetics.

The therapeutic system described above in U.S. Pat. No. 4,839,177 andU.S. Pat. No. 5,422,123 is characterised in that one part of said matrixis covered by an impermeable barrier (obtained by the application of apolymeric film which is insoluble in water and aqueous medium as in U.S.Pat. No. 4,839,177 or in that a layer of material and/or a polymericmaterial mix is applied by compression (possibly granulates obtained inaccordance with known techniques) thus giving impermeability and/or, inany case, impeding the release of the drug carried in the matrix formthe protected surface for a predeterminable time period (as in U.S. Pat.No. 5,422,123). The result is that the release of the active principlecarried in the hydrophilic matrix only occurs from the free surface ofthe layer containing the active substance in direct contact with thedissolution medium. Such a system is characterised in that the activeprinciple, carried in said pharmaceutical forms, is given up at avelocity which generally proves constant over time (zero releasekinetics) as is highlighted in the claims of the cited patent.

Other tablet formulations have provided for the liberation of one ormore drugs at different release rates (WO 94/06416) by appropriateformulation of the layers in the multi-layer tablet. Alternative phaseddrug release systems have described the use of an impermeable membraneto control the time of drug release (U.S. Pat. No. 5,487,901), acomplete coat of a biodegradable polymeric material (U.S. Pat. No.6,027,748), or a more substantial layer of controlled permeabilitymaterials (EP-A-0788790). Still further multi-layer tablets have beendescribed in which the tablet shows a high volume increase on contactwith the contents of the stomach so as to provide for prolonged gastricresidence times (EP-A-0795324).

However, in many treatment protocols, the patient must take drugs forextended time periods, for chronic disease treatment and must follow, attimes, complex posological patterns, taking two or more pharmaceuticalforms over 24 hours. Such complex and distinct therapeutic models arepoorly supported and infrequently followed by non-hospitalised patients;in fact, the withdrawal of the correct observance of the posologicalmodels is very frequent and well known in the case of outpatients, andsuch a withdrawal is directly proportional to the complexity and numberof administrations required or recommended during the day. For example,in the treatment of chronic diseases, for example hypertension theposology of the drugs must be adjusted in relation to the seriousness ofthe pathology and hence personalised to the specific therapeutic needsof the individual concerned.

Of importance to many pathological models, is the request by the medicalprofession to make available pharmaceutical forms with a verydifferentiated active principle content (so as to favour thepersonalisation of the posology), which however are able to release thedrug with similar or equivalent velocity and release kinetics,independent from the amount of active substance carried.

Therefore the availability of pharmaceutical forms which can releasedifferent dosages of the same drug at the same or similar velocity wouldprovide the medical profession with a solution, to an importanttherapeutic problem, of major social relevance for the type of therapyat which it is directed. Such dosage forms would allow for theoptimisation of drug use and biologically active substances in general.

It has now been discovered that utilising a particular formulation andpharmaceutical form consisting of a multi-layer tablet, preferablycontaining two or three layers, it is possible to obtain a similar oridentical release velocity, even if said tablet carries very differentamounts of the same active substance.

The originality of the new, prepared embodiment, in addition to themorphological and practical characteristics of the new therapeuticsystem are better illustrated in the following detailed description.

According to a first aspect of the invention there is provided amulti-layer tablet, in particular a multi-layer controlled-releasetablet, comprising:

-   -   (a) one active layer containing: (i) an active substance, (ii)        hydrophilic polymeric substances which swell and/or gel and/or        erode upon contact with aqueous liquids, (iii) lipophilic        substances, and (iv) adjuvant substances, wherein the weight        ratio of the hydrophilic polymeric substances to the lipophilic        substances contained in said active layer is in the range of        10:1 to 0.5:1; and    -   (b) one or more barrier layers containing one or more of:        hydrophilic polymeric substances which swell and/or gel and/or        erode upon contact with aqueous liquids, lipophilic substances,        and adjuvant substances.

Multi-layer tablets prepared in accordance with the present inventionare able to provide substantially equivalent (or identical) releasekinetics for the same active substance when formulated at differentamounts in the active substance containing layer in the multi-layertablet. The pharmaceutical tablets of the invention have the advantageof releasing the carried active substance in a programmed way,preferably also avoiding the phenomenon of dose dumping, and thereforebeing able to meet specific therapeutic needs with the gradual andcontrolled release of the active substance.

The multi-layer tablets of the present invention can be prepared astwo-layer tablets, three-layer tablets or greater numbers of layers ifrequired. At least one layer will contain the active substance to bereleased from the tablet and least one layer will be a barrier orsupport layer with respect to the active substance containing layer.Possible constructions of multi-layer tablets are shown in FIGS. 1 to 9.The tablets may have an overall substantially circular cross-section, orit may adopt a more oval cross-section or any other suitable geometricshape, for example rectilinear. The tablet may also be shaped as acaplet (capsule form tablet). As will be appreciated there are manypotential arrangements of the layers in multi-layer tablets.

The layer containing the active substance can be referred to as theactive layer, although, it should be noted that more than one activesubstance can be formulated in a tablet of the present invention. Thelayer that generally does not contain an active substance can bereferred to as a barrier layer or a support layer.

A simple two-layer tablet is shown in FIG. 1 where one lateral surfaceof the active substance containing layer (dotted) is covered by abarrier layer (hatched). A variation of this construction is shown inFIG. 2 where two barrier layers cover both exposed lateral surfaces ofthe active substance containing layer. In FIG. 3 a single barrier layercoats one lateral surface and the side of the active layer. The barrierlayer is shown as being present in the form of an annular ring in FIG. 4surrounding the active core and FIG. 5, an active core consisting of twoactive layers is shown surrounded by an annular ring of a barrier layer.

In FIG. 6 a three layer tablet is shown in which there is a firstbarrier layer (3) with an exposed upper lateral surface and sides, whichis adjacent to a second active layer (2) with both lateral surfacescovered and the side of the layer exposed, which is in turn adjacent toa second active layer (1) where the bottom lateral surface is exposedand the side is exposed. The two active layers may contain differentactive substances or the same active substance in different amounts.FIG. 7 shows an alternative arrangement of the FIG. 6 embodiment, wherethe active substance layer (5) is wholly within the barrier layer (6)and the second active substance layer (4). In FIG. 8, a similarthree-layer tablet is shown in which the barrier layer (8) is interposedbetween the two active substance containing layers (9) and (7).

Another three layer tablet (caplet) construction is also shown in FIG. 9in which the tablet has two external barrier layers (10, 12) and anactive substance layer (11) interposed between the barrier layers.

In some tablet configurations, the barrier layer may also contain anactive substance such that it acts as a barrier layer with respect to afirst active substance containing layer, but which itself is an activesubstance containing layer. Generally, in such embodiments, the activesubstance in the active layers is different in the separate layers,although arrangements in which the same active is present in theseparate active layers in different amounts can also be envisaged.

The barrier layer(s) are meant to limit the release surface of theactive layer, so as to allow that said carried active substance isreleased by the sole uncovered surface upon contact with the dissolutionmedium and/or the biological fluids according to kinetics that, invitro, can be programmed according to precise methods, as will behighlighted in the given examples of the present invention.

Any pharmaceutically active substance suitable for oral administrationin the form of a tablet can be formulated in a tablet of the presentinvention. An active substance is therefore a pharmaceutical (drug) witha therapeutic use, such substances also include those for administrationfor non-therapeutic uses, such as diagnosis of for dietary purposes.

Preferably the active substance may be one aimed at the treatment ofchronic diseases, for example, drugs acting on the cardiovascularsystem, anti-arrhythmics, cardiac stimulants, vasodilators, calciumantagonists, anti-hypertensives, for example anti-adrenergic substancesof central and peripheral action or substances acting on the arteriolarmusculature, analgesic substances, substances acting on therenin-angiotensin system, anti-hypertensives and diuretics inassociation, anti-Parkinson's Disease agents, diuretics and drugs forthe treatment of Alzheimer's disease, anti-histamines and/oranti-asthmatics.

Examples of active substances which may be used in such pharmaceuticalforms are: propranolol, atenolol, pindolol, ropinirole, prazosin,ramipril, spirapril; spironolactone, metipranolol, molsidomine,moxonidina, nadolol, nadoxolol, levodopa, metoprolol, timolol. In aparticular preferred embodiment, the active substance (i) comprises oris ropinirole, inclusive of pharmaceutically acceptable salts thereof.

Ropinirole, its chemical structure, processes for its preparation andtherapeutic uses thereof, are more fully described in EP-A-0113964 (seeExample 2), EP-A-0299602, EP-A-0300614, WO 91/16306, WO 92/00735 and WO93/23035, and the contents of which are hereby incorporated byreference. “Ropinirole” as mentioned herein is defined as includingpharmaceutically acceptable salts thereof Most preferably, theropinirole used in the tablet is in the form of the hydrochloride salt.Ropinirole is presently marketed as the HCl salt in an immediate-releasetablet for the treatment of Parkinson's Disease (see also EP-A-0299602).Ropinirole can be synthesised by the advantageous method described in WO91/16306.

In embodiments of the invention in which the active substance comprisesor is ropinirole, the amount of ropinirole present, inclusive ofpharmaceutically acceptable salts thereof, may be up to 12.0 mg,preferably from 0.75 mg to 12.0 mg, measured as the amount of ropinirolebase present, that is excluding any amount of acid (for example,hydrochloric acid, HCl) added to form any ropinirole salts. The amountof ropinirole present, inclusive of pharmaceutically acceptable saltsthereof, may be up to 12.0 mg, preferably from 0.75 mg to 12.0 mg,measured as the amount of ropinirole base present, per 150 mg of activelayer present. See Examples 13 to 18 hereinafter.

Analgesic substances include, but are not limited to, steroidalanti-inflammatory drugs, opioid analgesics, and non-steroidalanti-inflammatory drugs (NSAIDs). The analgesic substance may be anon-steroidal anti-inflammatory drug (NSAID), such as acetyl salicylicacid, salicylic acid, indomethacin, ibuprofen, naproxen, naproxensodium, flubiprofen, indoprofen, ketoprofen, piroxicam, diclofenac,diclofenac sodium, etodolac, ketorolac, or the pharmaceuticallyacceptable salts and/or derivatives or mixtures thereof.

Other suitable analgesic substances include, but are not limited toopioid analgesics such as alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tramadol, tilidine and pharmaceuticallyacceptable salts and/or derivatives or mixtures thereof.

Anti-hypertensive drugs may include, diltiazem, trapidil, urapidil,benziodarone, dipiridamole (dipyridamole), lidoflazine, naphthydrofuryloxalate, perhexeline maleate, oxyfedrine hydrochloride. Anti-histaminesand/or anti-asthmatics may include ephedrine, terfenadine, theophyllineor chlorpheniramine.

In any case the matrices can be prepared, carrying any type of activeprinciple for which pharmaceutical forms may be necessary capable ofreleasing also very different amounts of active substance with the samerelease kinetics.

In the tablets of the present patent application, the active substanceto be carried may have a very wide solubility interval in water, e.g.between 0.01 mg/L up to 3000 g/L, preferably between 10 mg/L up to 1000g/L (e.g. ropinirole has 133 g/L solubility), or between 0.01 mg/L up to100 g/L.

The active substance is preferably contained in a percentage between0.05% to 50% by weight of the active layer; more preferred ranges of theactive substances are 0.05% to 40%, 0.05% to 30%, 0.05% to 10%, 0.05% to20%.

Natural or synthetic hydrophilic polymeric substances, can be used inthe preparation of said active layer which are biocompatible and/orbiodegradable materials and pharmaceutically acceptable, e.g.polyvinylpyrrolidone in particular non-cross-linked polyvinylpyrrolidone(e.g. of molecular weight 30,000-400,000), hydroxypropylcellulose with amolecular weight of from 100,000 to 4,000,000, sodiumcarboxymethylcellulose (e.g. non-cross-linked, e.g. typical molecularweight 90,000-700,000), carboxymethylstarch, potassiummethacrylate-divinylbenzene copolymer, hydroxypropylmethylcellulose witha molecular weight between 2,000 and 4,000,000, polyethyleneglycols ofdifferent molecular weight preferably between 200 and 15,000 (morepreferably 1000-15000) and polyoxyethylenes of molecular weight up to20,000,000 (more preferably 400,000-7,000,000), carboxyvinylpolymers,poloxamers (polyoxyethylene-polyoxypropylene copolymer),polyvinylalcohols, glucanes (glucans), carrageenans, scleroglucanes(scleroglucans), mannans, galactomannans, gellans, xanthans, alginicacid and derivatives (e.g. sodium or calcium alginate, propylene glycolalginate), polyaminoacids (e.g. gelatin), methyl vinyl ether/maleicanhydride copolymer, carboxymethylcellulose and derivatives (e.g.calcium carboxymethylcellulose), ethylcellulose, methylcellulose, starchand starch derivatives, alpha, beta or gamma cyclodextrin, and dextrinderivatives (e.g. dextrin) in general. The hydrophilic polymericsubstance is therefore one which can be described as a controlledrelease polymer or a polymeric substance which is capable of achievingcontrolled release (CR).

More preferably for achieving advantageous controlled release of theactive substance the hydrophilic polymeric substances in the activelayer comprise one or more of the following: hydroxypropylcellulose witha molecular weight of from 100,000 to 4,000,000,hydroxypropylmethylcellulose (HPMC) with a molecular weight between2,000 and 4,000,000 (more preferably between 10,000 and 1,500,000molecular weight, still more preferably between 20,000 and 500,000molecular weight, most preferably about 250,000 molecular weight),ethylcellulose or methylcellulose. The most preferred controlled releasepolymer is HPMC.

Hydrophilic polymeric substances such as sodium carboxymethylcelluloseand/or calcium carboxymethylcellulose that act as viscosity-increasingagents/polymers or “cage-forming” components are also preferredcomponents e.g. of the active layer. The provision of theseviscosity-increasing polymers in the active layer is preferred becausethese help to reduce the “dose-dumping” effects occasionally seen withsoluble active substances (e.g. ropinirole) whereby a significantminority of the active substance can be released from the active layerin the first (say) hour after oral administration. Thus, it is preferredfor this purpose that the hydrophilic polymeric substances in the activelayer comprise sodium carboxymethylcellulose, carboxymethylcellulose ora derivative (e.g. calcium carboxymethylcellulose),hydroxypropylcellulose with a molecular weight of from 100,000 to4,000,000, a carboxyvinylpolymer, a carrageenan, a xanthan, alginic acidor a derivative (e.g. sodium or calcium alginate, propylene glycolalginate), ethylcellulose, methylcellulose, dextrin and/or maltodextrin.Most preferred for this purpose is sodium carboxymethylcellulose (NaCMC)(e.g. non-cross-linked, e.g. typical molecular weight 90,000-700,000).The present invention also comprehends the use of other equivalentpolymers able to act as viscosity-increasing agents and/or“cage-forming” components.

It is more preferred that the hydrophilic polymeric substances in theactive layer comprise both the above-mentioned preferred controlledrelease polymers and the above-defined viscosity-increasing polymers.Thus it is preferred that the hydrophilic polymeric substances in theactive layer comprise:

-   -   (a) one or more of the following: hydroxypropylcellulose with a        molecular weight of from 100,000 to 4,000,000,        hydroxypropylmethylcellulose (HPMC) with a molecular weight        between 2,000 and 4,000,000, ethylcellulose or methylcellulose;        and    -   (b) sodium carboxymethylcellulose, carboxymethylcellulose or        derivatives (e.g. calcium carboxymethylcellulose),        hydroxypropylcellulose with a molecular weight of from 100,000        to 4,000,000, a carboxyvinylpolymer, a carrageenan, a xanthan,        alginic acid or a derivative (e.g. sodium or calcium alginate,        propylene glycol alginate), ethylcellulose, methylcellulose,        dextrin and/or maltodextrin.

Thus, while the controlled release polymer (a) such as HPMC is stillswelling and/or gelling gradually in the first hour-or-so after oraladministration of the tablet, when it may be less effective incontrolling release of soluble active substances such as ropinirole fromthe active layer, the viscosity-increasing polymer (b) such as sodiumcarboxymethylcellulose (NaCMC) reduces the release of the activesubstance from the active layer. Without being bound by theory, ionicviscosity-enhancers like NaCMC might also to interact with thehydroxypropyl groups of, for example, HPMC to boost synergistically thehydration and swelling rate of HPMC leading to greater gel strength.

Thus, the most preferred combination is that the hydrophilic polymericsubstances in the active layer include (or are) HMPC and sodiumcarboxymethylcellulose, especially when the active substance has a high(e.g. from 10 mg/L to 1000 g/L) solubility in water, such as ropinirole.

Preferably, the hydrophilic polymeric substances have an HLB value of atleast 10 (see A. Gennaro and J. Remington, Remington's PharmaceuticalSciences, 18^(th) edition, Mack Publishing Company, Easton, Pa., 304(1990) and W. C. Griffin, J. Soc. Cosmetic Chemists, vol. 1, page 311,1949 for HLB values and measurement thereof). Said hydrophilic polymericsubstances make up between 1% and 75% of the weight of the active layer,but preferably are present in a percentage between 5% and 65% and/orbetween 30 and 75%, more preferably 43-75% or 43-67% or 43-65%. Any HPMCpresent in the active layer is preferably present in about 40-63 % byweight of the active layer. The viscosity-increasing polymers mentionedabove, such as sodium carboxymethylcellulose, if present are preferablypresent in up to 20% by weight of the active layer, more preferably(especially for NaCMC) 3-20%, 5-20%, 7-15%, or about 10% by weight ofthe active layer.

For all the polymers cited different types are commercially availablecharacterised by different chemical, physical, solubility andgelification properties. In particular, as regards,hydroxypropylmethylcellulose various types with a different molecularweight (between 1,000 and 4,000,000, preferably from 2,000 to 4,000,000,even more preferably between 10,000 and 1,500,000 molecular weight,still more preferably between 20,000 and 500,000 molecular weight, mostpreferably about 250,000 molecular weight) can be used and withdifferent degrees of substitution. Said types ofhydroxypropylmethylcellulose have differentiated characteristics beingmainly erodible or able to be gelled, depending on the viscosity and thedegrees of substitution (D.S.) present in the polymeric chain. GellableHPMCs (e.g. Methocel K grades) are preferable to erodible HPMCs (e.gMethocel E grades). The polyethyleneglycols and polyoxyethylenes showidentical behaviour: in fact, different hydrophilic and gelificationproperties correspond to different molecular weights.

The molecular weight of polymers and the 2% viscosity of polymers can bedirectly correlated (“METHOCEL™ in Aqueous Systems for Tablet Coating”,page 12, published by The Dow Chemical Company—www.dow.com—METHOCEL™ isa trademark of The Dow Chemical Company) where viscosity of a polymer isdefined as viscosity of a 2% aqueous solution at 20° C. measured as mPa.seconds. Viscosity is measured in Pascal seconds (SI units) or in poise(c.g.s. units), where 1 centipoise=10⁻³ Pa.sec. So for example,METHOCEL™ K100M has an approximate molecular weight of 246,000 and acorresponding 2% viscosity of 100,000 mPa.sec (based on an averageviscosity of 80,000 to 120,000 mPa.sec.); METHOCEL™ K4M has anapproximate molecular weight of 86,000 and a corresponding 2% viscosityof 4,000 mPa.sec; and METHOCEL∩ K100LV has an approximate molecularweight of 27,000 and a corresponding 2% viscosity of 100 mPa.sec. Forthis reason, the preferred molecular weight ranges of the polymericsubstances, for example the hydroxypropylmethylcellulose polymers canalso be defined in terms of viscosity.

One preferred viscosity range for the hydroxypropylmethylcellulosepolymers as defined above may be in the range of from 50 to 150,000mPa.sec, suitably 80,000 to 120,000 mPa.sec (e.g. K100M, as in theactive and barrier layers of Examples 13-21). This applies both to theactive layer (discussed above) or the barrier/support layer(s)(discussed below).

In an alternative embodiment, in order to obtain a faster release rate,the viscosity range for the hydroxypropylmethylcellulose polymers in theactive and/or barrier layer(s) may be in the range of from 50 to 25,000mPa.sec (including Methocels K4M, K15M, K100LV). In this embodiment,preferably some or all of the HPMC polymers have a viscosity in therange of from 1000 to 25,000 mPa.sec (including Methocels K4M & K15M butnot K100LV or K100M). More preferably, HPMC polymers having a viscosityin the range of from 1000 to 25,000 mPa.sec are present in the active orbarrier layer in a percentage of from 5 to 50% by weight of the activeor barrier layer. In particular, Examples 22 and 23 hereinafter have 10%and 40 weight % respectively of such HPMC (K4M) in their barrier layerswhich gives a slightly faster release profile in vitro than the ca. 45wt % K100M HPMC present in the barrier layers of Examples 13-18 and19-21, as inter alia the active substance e.g. ropinirole migratesfaster through the barrier layers. Preferably, the proportion oflow-viscosity HPMCs having from 50 to <1000 mPa.sec viscosity (includingMethocel K100LV) contained in the active or barrier layers is less than30% by weight of that layer—e.g. Example 22 has 20 wt. % of such HPMC(K100LV) as well as 10 wt % K4M HPMC in the barrier layer. Up to 30%low-viscosity HPMC in active or barrier layer can increase water uptakeand aid gelling, increasing the matrix viscosity and decreasing therelease rate, but greater amounts are not preferred.

In an alternative embodiment of the invention, there is provided atablet as previously defined, in which the active layer containspolymeric material with slow swelling and/or gellification and/orerosion and/or solubility properties.

A fundamental characteristic of the tablets of the present invention isthat, for the formulation both of the layer containing the activesubstance and the barrier layers, lipophilic substances are utilised,for example natural fats (coconut, soya, cocoa) as such or totally orpartially hydrogenated, beeswax, polyethoxylated beeswax, mono-, bi- andtri-substituted glycerides, glyceryl palmitostearate, glyceryl behenate(glyceryl tribehenate C₆₉H₁₃₄CO₆, e.g. Compritrol 888, where behenicacid=docosanoic acid=C₂₁H₄₃COOH), diethyleneglycol palmitostearate,polyethyleneglycol stearate, polyethyleneglycol palmitostearate,polyoxyethylene-glycol palmitostearate, glyceryl monopalmitostearate,cetyl palmitate, mono- or di- glyceryl behenate (glyceryl mono-behenateor glyceryl di-behenate), fatty alcohols associated with polyethoxylatefatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturatedfatty acids and their hydrogenated derivatives, hydrogenated castor oiland lipophilic substances in general. In certain preferred embodimentsof the invention, the lipophilic substances are selected fromhydrogenated castor oil and glyceryl behenate.

Preferably, the lipophilic substances have an HLB value of less than 10,more preferably, less than 5.

Preferably, the lipophilic substances make up between 1% and 70% of theactive layer weight, but preferably are present in a percentage between5% and 55%, more preferably 5-35%.

The weight ratio between the content of hydrophilic polymeric substancesand lipophilic substances, in the layer containing the active substance,is between 10:1 and 0.5:1 (i.e. in the range of 10:1 to 0.5:1), suitablybetween 10:1 and 1:1 (i.e. in the range of 10:1 to 1:1), but preferablybetween 7:1 and 1:1 (i.e. in the range of 7:1 to 1:1).

Besides the previously cited hydrophilic polymers and the lipophilicsubstances, lipophilic and/or substances of amphiphilic nature may beused in the formulation, in which the hydrophilic portion can berepresented by glycerol molecules or other polyalcohols orpolyethyleneglycol molecules (PEG) of molecular weight between 100 and10,000, whereas the lipophilic part is represented by unsaturated and/orsaturated fatty acids, in hydrogenated vegetable oil form. Theassociation of the hydrophilic portion with the lipidic chain isobtained by esterification reactions or partial alcoholysis ofhydrogenated vegetable oils by PEG molecules or glycerol or otherpolyol. In this way compounds characterised by a different degree ofhydrophilicity are obtained that can be assessed by measuring theHydrophilic-Lipophilic Balance (HLB). Triglycerides are available withan HLB value between 1 and 2, diglycerides with HLB between 2 and 3,monoglycerides with HLB between 3 and 4, PEG diesters with HLB between 6and 15, PEG monoesters with HLB between 10 and 17. In practice,increasing the HLB values increases the hydrophilic tendency and,obviously, decreases the lipophilic tendency. Tablets according to thepresent invention may therefore also contain polymeric substances of alipophilic nature.

Finally, adjuvants normally used in the pharmaceutical technique may beemployed, for example, diluents, binders, lubricants, glidants andnon-stick types, for example, starch, mannitol, lactose, sorbitol,xylitol, talc, stearic acid, sodium benzoate, magnesium stearate,colloidal silica, maltodextrin, and other excipients known to the expertin the field.

In order to promote the penetration of water and/or aqueous fluids inthe layer or nucleus, hydrophilic diluents, for example, mannitol,lactose, starches of different origins, sorbitol, xylitol areintroduced, or substances with wetting properties and/or those generallyencouraging the penetration of water in the solid are preferably carriedin the formulation.

Moreover, diluents, binders, lubricants, buffers, non-stick substances,glidants and plasticising substances can be employed as well as otherscapable of giving said layer the desired characteristic as will bebetter illustrated in the examples quoted later on.

Said adjuvants are preferably contained in a percentage between 5% to50%, preferably from 10% to 40% or 20 to 50 % or 20% to 35% of theweight of said active layer. The weight ratio of the active substance(i) to that of the adjuvant component (iv) in the active. layer can bein the range of from 0.001:1 and 4:1, suitably of from 0.003:1 to 3:1.

The polymeric substances employed for the preparation of the barrierlayer in association with other adjuvants, are able to provide a barrier(applied by compression) which proves impermeable to the carried activesubstance in the underlying layer for a time period that strictlydepends on its composition, which can vary from 1 hour to approx. 20-24hours or more. In such case, the release of the active substance in thestated periods (e.g. during the first hour after oraladministration/immersion in aqueous fluids) occurs only from the surfaceof the tablet not covered by the barrier. “impermeability” is to beconstrued accordingly. Preferably, during the first hour after oraladministration or immersion in aqueous liquids (e.g. water), release ofthe active substance occurs substantially only from the surface of thetablet not covered by the barrier.

To test the impermeability of the barrier layer to the release of theactive substance, various suitable tests can be conceived by personsskilled in the art of pharmaceutical tablet formulation. However, onesuch test may be based on selective coating of the free surfaces of theactive layer with a suitable substance, such as an enteric coat (forexample, “Eudragit”), or a waxy material (for example, beeswax) suchthat normal release of active does not occur through these surfaces. Anin vitro dissolution test can then be performed in which the dissolutionfluid can be sampled at appropriate time points. In this way, the pointin time can be determined at which the active substance is releasedthrough the barrier layer through the interaction of the componentsubstances of the barrier layer with the aqueous environment (that is tosay the point in time at which the polymers of the barrier layer permitrelease). Alternatively, the free surfaces of the barrier layer(s) canbe selectively coated as above and a dissolution test performed. Therelease profile obtained would correspond to that of an uncoated tabletup to the point in time at which the active substance was able topermeate the barrier layer and be released from the uncoated tablet.

As noted above, the barrier layer may be superposed over one or morefree surfaces of the active layer in the tablet. Generally, the barrierlayer will form a layer to cover one or more lateral surfaces of theactive layer. In a preferred embodiment of the present invention,tablets are provided in which one or more barrier layers are used tocover one or both surfaces or bases of the active layer. Sucharrangements therefore provide for a bi-layer or a tri-layer tablet.

The natural synthetic hydrophilic polymeric materials, usable in theformulation of the barrier layer, can be chosen from among those listedfor the preparation of the active layer. Said polymeric substances canbe present in a percentage of 5 to 90%, with respect to the total weightof said layer but, preferably, between 25% and 85%.

Said polymeric substances, utilised individually or mixed together andmixed with the lipophilic substances, are able to bring about theimpermeability in the release of the carried active principle in theunderlying layer for a time interval that can vary from 1 hours toapprox. 20-24 hours or more, depending on the composition.

For the preparation of the barrier layer such lipophilic substances canbe chosen from those listed for preparation of the active layer. Saidlipophilic substances can be present in a percentage between 5% and 70%with respect to the total weight of said layer but, preferably, between5% and 55%.

The weight ratio of hydrophobic swelling and/or gelling and/or erodiblepolymeric substances to lipophilic substances contained in the barrierlayer can be in the range of 1:1 and 7.5:1, suitably of from 1.5:1 to4:1, and preferably from 2:1 to 3.5:1.

Said barrier layer(s), applied by compression, can have a thicknessbetween 0.1 and 4.5 mm. The matrix preparation can be carried out by thecompression of powder or granular mixtures, for example by blendingfollowed by dry compression or wet granulation followed by compression,and preferably working between 1000 and 5000 Kg/cm².

In general, tabletting can be through direct compression, i.e. a mixtureof dry powders being compressed, but this can sometimes cause qualityissues such as segregation, poor flow etc. These issues can be improvedby the use of granulation techniques on all or part of the constituentmix.

Granulation is a process in which powder particles are agglomeratedtogether to form granules. This can be carried out to:

1. improve the flow properties of a powder mixture,

2. prevent segregation of the constituent powders (improve homogeneity),

3. improve compression characteristics,

4. achieve densification of powder mixes, and/or

5. achieve alteration of particle size/shape/hydrophilic properties

The tablet of the invention may be prepared by dry granulation. DryGranulation is granulation by compression of powders by either sluggingor roller compaction. It is essentially a densification process.

Slugging is where a crude compact (slug) is produced to a setweight/thickness for a given diameter of slug. These slugs are thenreduced by either grating or commuting mill to produce granules of therequired particle size/range.

Roller compaction or Chilsonating is where a powder mix is forced via anauger between 2 rollers (which can be smooth or grooved). Compaction ofthis material is controlled by the feed rate to the rollers and thehydraulic force of the rollers being pushed together. The resultingcompact (called a ribbon or strip) is then reduced by either grating orcommuting mill to produce granules of the required particle size/range.

Where dry granulation is used, the adjuvants often differ slightlycompared to wet granulation. For example, instead of lactose monohydrate(often used in wet granulation), one preferably uses spray-dried lactosepreferably containing amorphous lactose (e.g. Fast-Flo lactose, Seppic,Paris, France).

However, the tablet of the invention is preferably prepared by wetgranulation. Wet Granulation is the most widely used granulationtechnique, and involves powder densification and/or agglomeration by theincorporation of a granulation fluid/medium to the powder mix. Wetgranulation can be aqueous-based or solvent-based, e.g. based on organicsolvents. Shear is dependent on the speed of the granulator paddle/bladethrough the powder. Various mixer designs are available, for example:

-   -   Wet High Shear, (rotating high shear forces (Fielder))    -   Wet Low Shear, (rotating low shear forces (Planetary mixer))    -   Wet Low Shear Tumble, (spraying in to tumble mixer with/without        intensifier bar)    -   Extrusion, (Wet solids pushed through classified screen)    -   Rotary Granulators, (Spheronisation, Marumerisation—spinning        disk or walls of a vessel)    -   Spray granulation in a fluidised Bed, or    -   Spray dry granulation.

For the formulation of said layer-barrier, which can be applied bycompression, possible adjuvants, in particular diluents, include thosetraditionally used in the preparation of solid forms. For examplemagnesium stearate, stearic acid, sodium stearate, talc, sodiumbenzoate, boric acid, polyethylene glycols and/or colloidal silica canbe employed.

In addition diluent, lubricating, non-stick and glidant substances andother substances may be used capable of giving said layer the desiredcharacteristic, as will be better illustrated in the examples quotedlater on. Other possible components include substances able to impart acolour to the eventual tablet layer prepared and formulated in themulti-layer tablet, for example iron oxide (yellow ferric oxide).

In addition a covering could be applied to said finished tablets by acoating process and/or any other process well known to experts in thefield. An example of a coating is “OPADRY OY-S-28876 WHITE”. OPADRYOY-S-28876 WHITE is 63% HPMC 2910 6cP, 7% PEG 400, 30% TiO2. Red/pink(0.01-0.25%) and/or yellow (0.1 to 1.5%) colourings can also be added(iron oxides), the HPMC varying between 61-66%. An alternative bluecoating uses 31-32% each of HPMC 2910 3cP and HPMC 2910 5cP, 8% PEG400,23-24% TiO2, 1% polysorbate, and indigotine as blue dye at 4-5%.

A colourant layer or a film of gastroresistant and enterosolublepolymeric material may also be applied to said finished tablets, so asto allow the activation of the system only after the tablet has reachedthe duodeno-intestinal tract. Pharmaceutical systems of the latter typecan be utilised for the accomplishment of tablets specifically designedto release the active principle in the latter part of the intestinaltract i.e. at colon level. In order to attain gastroresistance,polymeric materials such as cellulose acetophthalate, celluloseacetopropionate, cellulose trimellitate, polymers and acrylic andmethacrylic copolymers can be used of different molecular weights andwith solubility which depends on different pH values. Said materials canbe applied to the finished pharmaceutical form (active layer and thebarrier layer(s)) by the classical coating process, utilising solutionsin organic solvents or aqueous dispersions and spraying or fluidised bednebulisation. Said gastro-resistant and enterosoluble materials canlikewise be utilised in association with retarder polymers.

One innovative embodiment is characterised in that is possible toachieve the claimed therapeutic system by utilising the productiontechnologies currently in use, i.e. the system may be immediately set upat industrial level.

One preferred embodiment of a tablet of the present invention comprisesa tablet as previously described in which the active layer consists ofcomponents (i) to (iv) wherein the active agent is present in a weightpercentage of 0.05% to 20% by weight of the active layer, the adjuvantsubstances are present in a weight percentage of 5% to 50% by weight ofthe active layer, and the weight ratio of the hydrophilic polymericsubstances to the lipophilic substances is in the range of from 7:1 to1:1.

Alternatively, the active layer consists essentially of components (i)to (iv) wherein the active agent is present in a weight percentage of0.05% to 20% by weight of the active layer, the adjuvant substances arepresent in a weight percentage of 5% to 50% by weight of the activelayer, and the weight ratio of the hydrophilic polymeric substances tothe lipophilic substances is in the range of from 7:1 to 1:1.

In certain preferred embodiments, the hydrophilic polymeric substancemay comprise hydroxypropylmethylcellulose of molecular weight 2,000 to4,000,000, sodium carboxymethylcellulose or calciumcarboxymethylcellulose.

In embodiments in which the active substance is ropinirole, the tabletmay be characterised by comprising (i) ropinirole present in a weightpercentage of 0.05% to 20% by weight of the active layer, (ii) thehydrophilic polymeric substance being hydroxypropylmethylcellulose,sodium carboxymethylcellulose or calcium carboxymethylcellulose. (iii)the lipophilic substance being hydrogenated castor oil or glycerylbehenate, and (iv) the adjuvant substances being present in a weightpercentage of 5% to 50% by weight of the active layer, in which theweight ratio of the hydrophilic polymeric substances to the lipophilicsubstances being in the range of from 7:1 to 1:1.

The present invention also extends to methods of treatment comprising atablet as herein described. According to a second aspect of theinvention there is provided a method of treating a disease, the methodcomprising the administration of a tablet as defined herein to apatient/human in need thereof. In a preferred embodiment the diseasetreated is Parkinson's Disease where the active substance comprises oris ropinirole or another therapeutic agent for the treatment of thiscondition. According to such methods, especially with ropinirole, one ormore multi-layer tablets can be administered once per day to the humanneed of such treatment, or a single multi-layer tablet can beadministered once per day. The controlled-release ropinirole tablet ofthe present invention is expected to be advantageous compared to themarketed ropinirole immediate-release (IR) formulation because it shouldallow a more constant and/or lower systemic concentration/C_(max) over a24-hr period, avoids the necessity with the IR tablet of takingropinirole three times a day, and should avoid some of the side-effectswhich are possible when IR ropinirole is administered. See especiallythe advantageous approx. 24 hour in vitro release shown inter alia inropinirole Examples 13-18 hereinafter: this is near-optimal forParkinson's disease.

The invention also provides the use of a tablet as herein defined,wherein the active substance comprises or is ropinirole, in themanufacture of a medicament for the treatment of Parkinson's disease ina human. The invention also provides such a tablet for use in thetreatment of Parkinson's disease.

Preferred features for the second and subsequent aspects of theinvention are as for the first aspect mutatis mutandis.

The invention will now be further described by way of reference to thefollowing Examples and Figures which are provided for the purposes ofillustration only and are not to be construed as being limiting on theinvention. Reference is made to a number of Figures in which:

FIG. 1 shows a transverse section through a bilayer tablet in which thebarrier layer is shown by hatching and the active substance containinglayer by dots.

FIG. 2 shows a transverse section through a trilayer tablet which hasupper and lower barrier layers and a central active layer.

FIG. 3 shows a transverse section through a two-layer tablet, in whichthe barrier layer coats a lateral surface and the side of the activelayer.

FIG. 4 shows a transverse section through a two-layer tablet in whichthe barrier layer is present as an annular ring around the active core.

FIG. 5 shows a transverse section through a tablet of FIG. 4 in whichthe active core consists of two different active layers.

FIG. 6 shows a transverse section through a trilayer tablet in which thebarrier layer (3) is superposed on active layer (2), which in turn issuperposed on active layer (1).

FIG. 7 shows a transverse section through a trilayer tablet in which thefirst active layer (5) is contained within barrier layer (6) and asecond active layer (4).

FIG. 8 shows a transverse section through a trilayer tablet in which thebarrier layer (8) is present interposed between active layers (9) and(7).

FIG. 9 shows plan, side elevation and end elevation views of a threelayer caplet, in which an active substance layer (11) is interposedbetween barrier layers (10,12); a cross-sectional view is shown throughline X-X.

FIG. 10 shows a dissolution profiles of comparison, replication batchesat dosages of 0.75 mg ropinirole measured as effective free base toinvestigate the influence of coating on release—results shown for tabletP00K39E shown as “□”, tablet P00K40E shown as “⋄”, tablet P00K41E shownas “Δ”, tablet C511 shown as “▪”, tablet C519 shown as “♦”, and tabletC529 shown as “▴”. Results shown as percentage drug released (%) overtime (hours).

FIG. 11 shows a dissolution profiles of comparison, replication batchesat dosages of 6 mg ropinirole measured as effective free base toinvestigate the influence of coating on release—results shown for tabletP00K45E shown as “□”, tablet P00K46E shown as “⋄”, tablet P00K47E shownas “Δ”, tablet C530 shown as “▪”, tablet C531 shown as “♦”, and tabletC532 shown as “▴”. Results shown as percentage drug released (%) overtime (hours).

FIG. 12 shows a dissolution profiles of comparison, replication batchesat dosages of 12 mg ropinirole measured as effective free base toinvestigate the influence of coating on release—results shown for tabletP00K42E shown as “□”, tablet P00K43E shown as “⋄”, tablet P00K44E shownas “Δ”, tablet C512 shown as “▪”, tablet C534 shown as “♦”, and tabletC535 shown as “▴”. Results shown as percentage drug released (%) overtime (hours).

FIG. 13 shows dosage influence on coated tablet displayed as acomparison of dissolution profiles of ropinirole at dosages of 0.75 mg,6 mg and 12 mg measured as free base (results of replication batches).Results shown as percentage drug released (%) over time (hours), wheretablets C511, C519 and C529 are 0.75 mg ropinirole shown as “—”, wheretablets C530, C531 and C532 are 6 mg ropinirole shown as

and where tablets C512, C534 and C535 are 12 mg ropinirole shown as

EXAMPLE 1 Systems Consisting of a Single Two-Layer Tablet—4.0 mgPindolol

In Example 1, the first layer contains 4 mg of pindolol (slow release);the second layer consists of a “barrier” layer.

1(a) Preparation of the Granulate Utilised for the Preparation of theLayer Containing 4.0 mg of Slow Release Pindolol.

Amount Component (mg) Pindolol 4.0 mg Mannitol (C. Erba, Milan, I) 21.0mg Hydroxypropylmethylcellulose (HPMC) (Methocel ® 63.0 mg K 100 M,Colorcon, Orpington, UK) (48 wt %) Glyceryl behenate (Compritol 888Gattefossé, St. 35.0 mg Priest; F) Polyvinylpyrrolidone (PVP)(Plasdone ® K29-32, 5.6 mg I.S.P.) (4.2%) Magnesium stearate (C. Erba,Milan, I) 1.4 mg Colloidal silica (Syloid 244, Grace GmbH, Worms, D) 1.4mg Total 131.4 mg

In total, the active layer contains 52.2 weight % of gellable, swellableand/or erodible hydrophilic polymers (PVP+HPMC).

Mix pindolol, mannitol, hydroxypropylcellulose and glyceryl behenate,wet with an aqueous solution of 20% polyvinylpyrrolidone. Pass over a25-mesh sieve, desiccate in a fluid-bed desiccator (Aeromatic mod.Strea) until constant weight is reached, pass over the same mesh sieveagain. Add the lubricant and silica and mix in turbula for 10 minutes.In this way a granulate (granulate 1(a)) is obtained with good flow(slide) and compaction properties. The granulate is subjected to thecompression stage as described later on.

1(b) Preparation of the Granulate Making up the Second Layer(Barrier-Layer)

Component Amount Hydroxypropylmethylcellulose (Methocel ® K 100 M,45.00% Colorcon, Orpington, UK) Glyceryl behenate (Compritol 888Gattefossé, St. Priest; F) 25.00% Lactose monohydrate 23.30%Polyvinylpyrrolidone (Plasdone ® K29-32, I.S.P.) 5.00% Yellow iron oxideFCF aluminium lake (Colorcon, Orpington, 0.18% UK) Carmine-indigoaluminium lake 20% (Colorcon, Orpington, UK) 0.12% Magnesium stearate(USP grade, C. Erba, Milan, I) 1.00% Colloidal silica (Syloid 244, GraceGmbH, Worms, D) 0.40%

Mix hydroxypropylmethylcellulose, glyceryl behenate and lactose,carefully disperse the dyes. Wet with an aqueous solution of 5%polyvinylpyrrolidone. Pass over a 25-mesh sieve, desiccate in an oven(stove) at 30° C. for approximately 2 hours. Pass over the 25-mesh sieveagain. Desiccate until constant weight is reached. Add the colloidalsilica and magnesium stearate to the granulate obtained and mix inturbula for 15 minutes. In this way a granulate (granulate 1(b)) isobtained with good slide and compaction properties. The granulate issubjected to the compression stage as described later on.

1(c) Preparation of the Two-Layer Systems (by Compression).

The granulates, obtained as previously quoted and according to wellknown models to all experts in the field, are loaded in the feedboxes ofa rotary compressing machine suitable for producing multi-layer tablets(e.g. Manesty Layer-Press, Liverpool, UK). In particular, the granulatedescribed in section 1(b) is loaded in the first; whereas the granulateas described in section 1(a) is loaded in the second feedbox. Thecompressing machine is equipped with 9 mm diameter circular concavepunches.

The machine is set so as to produce two-layer systems consisting of aninitial 100 mg of granulate barrier, a second layer of 131.4 mgcontaining the active principle (equal to 4.0 mg of pindolol.). Workingas previously described, two-layer tablets are obtained with a meanweight of 231.4 mg, each containing 4.0 mg active principle. Table 1contains the data relating to the release verification of the activeprinciple from the tablets in Example 1.

EXAMPLE 2 Systems Consisting of a Single Two-Layer Tablet—8.0 mgPindolol

In Example 2, the first layer (slow release) contains 8 mg of pindolol;the second layer consists of a “barrier” layer.

A granulate is prepared as described in Example 1, in section 1(a), theonly alteration being to double the amount of carried active principle.The second layer (barrier) is kept identical both qualitatively andquantitatively, as described in Example 1 in section 1(b). Working asdescribed in section 1(c), two-layer tablets are prepared consisting ofan initial amount of 100 mg of granulate barrier (barrier), a secondlayer of 135.4 mg containing the active principle (equal to 8.0 mg ofpindolol). Hence two-layer tablets are obtained with a mean weight of235.4 mg, each containing 8.0 mg of active principle. Table 1 containsthe data relating to the release verification of the active principlefrom the tablets in Example 2.

EXAMPLE 3 Systems Consisting of a Single Two-Layer Tablet—16.0 mgPindolol

In Example 3, the two-layer tablet system is as described in Examples 1and 2 but containing 16.0 mg of pindolol.

A granulate is prepared as described in Example 1, in section 1(a), theonly alteration being to carry 16 mg of active principle thus 143.4 mgof granulate contain 16.0 mg of pindolol. The second layer (barrier) iskept identical both qualitatively and quantitatively, as described inExample 1 in section 1(b). Working as described in section 1(c),two-layer tablets are prepared consisting of an initial amount of 100 mgof granulate barrier, a second layer of 143.4 mg containing the activeprinciple (equal to 16.0 mg of pindolol). Hence two-layer tablets areobtained with a mean weight of 243.4 mg, each containing 16.0 mg ofactive principle. Table 1 contains the data relating to the releaseverification of the active principle from the tablets in Example 3.

EXAMPLE 4 Systems Consisting of a Single Two-Layer Tablet—24 mg Pindolol

In Example 4, the two-layer tablet system is as described in Examples 1and 2 but containing 24.0 mg of pindolol.

A granulate is prepared as described in Example 1, in section 1(a), theonly alteration being to carry 24 mg of active principle; thus 151.4 mgof granulate contain 24.0 mg of pindolol. The second layer (barrier) iskept identical both qualitatively and quantitatively, as described inExample 1 in section 1(b). Working as described in section 1(c),two-layer tablets are prepared consisting of an initial amount of 100 mgof granulate barrier, a second layer of 151.4 mg containing the activeprinciple (equal to 24.0 mg of pindolol). Hence two-layer tablets areobtained with a mean weight of 251.4 mg, each containing 24.0 mg ofactive principle. Table 1 contains the data relating to the releaseverification of the active principle from the tablets in Example 4.

EXAMPLE 5 Systems Consisting of a Single Two-Layer Tablet—32.0 mgPindolol

In Example 5, the two-layer tablet is as described in Examples 1 and 2but containing 32.0 mg of pindolol.

A granulate is prepared as described in Example 1, in section 1(a), theonly alteration being to carry 32.0 mg of active principle; thus 159.4mg of granulate contain 32.0 mg of pindolol and 43 weight % of totalgellable, swellable and/or erodible hydrophilic polymers (PVP+HPMC) or40 wt % (more exactly 39.5 wt %) HPMC.

The second layer (barrier) is kept identical both qualitatively andquantitatively, as described in Example 1 in section 1(b). Working asdescribed in section 1(c), two-layer tablets are prepared consisting ofan initial amount of 100 mg of granulate barrier, a second layer of159.4 mg containing the active principle (equal to 32.0 mg of pindolol).Hence two-layer tablets are obtained with a mean weight of 259.4 mg,each containing 32.0 mg of active principle. Table 1 contains the datarelating to the release verification of the active principle from thetablets in Example 5.

Dissolution Test of Tablets Prepared in Examples 1 to 5

To assess the release characteristics of the active principle from thetwo-layer tablets, quoted in Examples 1-5, equipment 2 is utilised,paddle (USP XXIII), working at 100 r.p.m. and utilising as dissolutionfluid 900 mL of 0.1M hydrochloric acid at 37° C. The release of theactive principle is followed by HPLC assessment at 227 nm utilising anautomatic sampling and reading system. The results of the experimentscarried out are quoted in Table 1

TABLE 1 TIME Percentage Released (hours) Example 1 Example 2 Example 3Example 4 Example 5 1 22.2 19.4 22.4 23.3 23.8 2 34.0 32.2 33.2 34.234.5 4 50.2 48.7 49.7 52.2 51.7 6 63.5 61.5 63.0 64.1 64.0 8 72.7 72.173.4 74.9 74.2 10 82.8 81.6 81.9 83.5 82.9 12 88.7 87.4 88.2 90.7 89.816 96.3 95.0 95.9 96.6 97.1 20 100.3 99.2 98.9 100.8 100.1

It is possible to point out that the release of the drug from theprepared systems is slowed down and the release of the whole drug takesapproximately 20 hours. In addition, it is clear that the releasekinetics are not substantially modified at any content level of activesubstance in the tablets. Such behaviour is in accordance with thepresent invention.

EXAMPLE 6 Systems Consisting of a Three-Layer Tablet—4 mg Molsidomine

In Example 6, a three-layer tablet is prepared in which the first layerconsists of 80 mg of a “barrier” layer, the second layer (slow release)contains 4 mg of molsidomine; the third layer consists of 100 mg of a“barrier layer”.

6(a) Preparation of the Granulate Utilised for the Preparation of theLayer Containing 4.0 mg of Slow Release Molsidomine.

Amount Component (mg) Molsidomine 4.00 mg Mannitol (C Erba, Milan, I)5.00 mg Hydroxypropylmethylcellulose (Methocel ® K 100 M, 60.00 mgColorcon, Orpington, UK) (63 wt %) Glyceryl behenate (Compritol 888Gattefossé, St. Priest; 20.00 mg F) Polyvinylpyrrolidone (Plasdone ®K29-32, I.S.P.) 3.70 mg Magnesium stearate (USP grade, C. Erba, Milan,I) 1.00 mg Colloidal silica (Syloid 244, Grace GmbH, Worms, D) 1.63 mgTotal 95.33 mg

In total, the active layer contains 66.8 weight % (i.e. 67 wt %) ofgellable, swellable and/or erodible hydrophilic polymers (PVP+HPMC).

Mix molsidomine, mannitol, hydroxypropylcellulose and glyceryl behenate,wet with a 20% solution of polyvinylpyrrolidone. Pass over a 25-meshsieve, desiccate in a fluid-bed desiccator (Aeromatic mod. Strea) untilconstant weight is reached, pass over the same mesh sieve again. Add thesilica and mix in a cubic mixer for 45 minutes, then add the magnesiumstearate and mix for a further 15 minutes. In this way a granulate(granulate 6(a)) with good slide and compaction properties. Thegranulate is subjected to the compression stage as described later on.

6(b) Preparation of the Granulate Making Up the Barrier-Layers.

Component Amount Hydroxypropylmethylcellulose (Methocel ® K 100 M,39.88%  Colorcon, Orpington, UK) Glyceryl behenate (Compritol 888Gattefossé, St. Priest; F) 13.50%  Lactose monohydrate 39.88% Polyvinylpyrrolidone (Plasdone ® K29-32, I.S.P.) 5.00% Yellow iron oxideFCF (Sicovit Gelb 10-BASF Koln; D) 0.24% Magnesium stearate (USP grade,C. Erba, Milan, I) 1.00% Colloidal silica (Syloid 244, Grace GmbH,Worms, D) 0.50% Total  100%

Mix hydroxypropylmethylcellulose, glyceryl behenate and lactose,carefully disperse the dye. Wet with a 5% aqueous solution ofpolyvinylpyrrolidone. Pass over a 25-mesh sieve, desiccate in an oven(stove) at 30° C. for approximately 2 hours. Pass over a 25-mesh sieveagain. Desiccate until constant weight is reached. Add the colloidalsilica and magnesium stearate to the granulate obtained and mix inturbula for 15 minutes. In this way a granulate (granulate 6(b)) isobtained with good slide and compaction properties. The granulate issubjected to the compression stage as described later on.

6(c) Preparation of the Three-Layer Systems (by Compression).

The granulates, obtained as previously quoted and according to wellknown models to all experts in the field, are loaded in the feedboxes ofa rotary compressing machine suitable for producing three-layer tablets(e.g. Manesty Layer-Press LP 39, Liverpool, UK). In particular, thegranulate described in section 6(b) is loaded in the first and thirdfeedboxes; whereas the granulate as described in section 6(a) is loadedin the second feedbox. The compressing machine is equipped with 8 mmdiameter circular concave punches.

The machine is set so as to produce three-layer systems consisting of aninitial 80.0 mg of granulate barrier, a second layer of 95.33 mgcontaining the active principle (equal to 4.0 mg of molsidomine) and athird layer of 100.0 mg of granulate barrier. Working as previouslydescribed, three-layer tablets are obtained with a mean weight of 275.33mg, each containing 4.0 mg active principle. Table 2 contains the datarelating to the release verification of the active principle from thetablets in Example 6.

EXAMPLE 7 Systems Consisting of a Single Three-Layer Tablet—8 mgMolsidomine

In Example 7, the first layer consists of 80 mg of a “barrier” layer,the second layer (slow release) contains 8 mg of molsidomine; the thirdlayer consists of 100 mg of a “barrier” layer.

A granulate is prepared as described in Example 6, in section 6(a), theonly alteration being to double the amount of carried active principle;such a granulate makes up the second layer of the three layer tablet.For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example6 in section 6(b). The compressing machine is equipped with 8 mmdiameter circular concave punches.

The machine is set so as to produce three-layer systems consisting of aninitial 80.0 mg of granulate barrier, a second layer of 99.33 mgcontaining the active principle (equal to 8.0 mg of molsidomine) and athird layer of 100.0 mg of granulate barrier. Working as previouslydescribed, three-layer tablets are obtained with a mean weight of 279.33mg, each containing 8.0 mg of active principle. Table 2 contains thedata relating to the release verification of the active principle fromthe tablets in Example 7.

EXAMPLE 8 Systems Consisting of a Single Three-Layer Tablet—16 mgMolsidomine

In Example 8, the first layer consists of 80 mg of a “barrier” layer,the second layer (slow release) contains 16 mg of molsidomine; the thirdlayer consists of 100 mg of a “barrier” layer. A granulate is preparedas described in Example 6, in section 6(a), the only alteration being todouble the amount of carried active principle; such a granulate makes upthe second layer of the three layer tablet.

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example6 in section 6(b). The compressing machine is equipped with 8 mmdiameter circular concave punches. The machine is set so as to producethree-layer systems consisting of an initial 80.0 mg of granulatebarrier, a second layer of 107.33 mg containing the active principle(equal to 16.0 mg of molsidomine) and a third layer of 100.0 mg ofgranulate barrier. Working as previously described, three-layer tabletsare obtained with a mean weight of 287.33 mg, each containing 16.0 mg ofactive principle. Table 2 contains the data relating to the releaseverification of the active principle from the tablets in Example 8.

EXAMPLE 9 Systems Consisting of a Single Three-Layer Tablet—20 mgMolsidomine

In Example 9, the first layer consists of 80 mg of a “barrier” layer,the second layer (slow release) contains 20 mg of molsidomine; the thirdlayer consists of 100 mg of a “barrier” layer. A granulate is preparedas described in Example 6, in section 6(a), the only alteration being todouble the amount of carried active principle; such a granulate makes upthe second layer of the three layer tablet. For the first and thirdlayer (barrier) a qualitatively and quantitatively identical granulateis employed, as described in Example 6 in section 6(b). The compressingmachine is equipped with 8 mm diameter circular concave punches.

The machine is set so as to produce three-layer systems consisting of aninitial 80.0 mg of granulate barrier, a second layer of 111.33 mgcontaining the active principle (equal to 20.0 mg of molsidomine) and57.2 weight % of gellable, swellable and/or erodible hydrophilicpolymers (PVP+HPMC) or 54 wt % HPMC, and a third layer of 100.0 mg ofgranulate barrier. Working as previously described, three-layer tabletsare obtained with a mean weight of 291.33 mg, each containing 20.0 mg ofactive principle. Table 2 contains the data relating to the releaseverification of the active principle from the tablets in Example 9.

Dissolution Test of Tablets Prepared in Examples 6 to 9

To assess the release characteristic s of the active principle from thethree-layer tablets, quoted in Examples 6 to 9, equipment 2 is utilised,paddle (USP XXIII), working at 100 r.p.m. and utilising as dissolutionfluid 900 mL of distilled water at 37° C. The release of the activeprinciple is followed by U.V. spectrophotometric assessment at 311 nmutilising an automatic sampling and reading system. The results of theexperiments carried out are quoted in Table 2

TABLE 2 TIME Percentage Released (hours) Example 6 Example 7 Example 8Example 9 1 12.3 11.4 11.9 12.6 2 19.6 20.7 18.8 21.2 4 32.7 33.8 31.533.0 6 41.5 43.0 42.5 43.1 8 52.8 54.2 53.0 54.5 10 64.0 66.5 65.3 63.612 74.7 76.4 75.2 77.0 16 88.4 89.6 86.8 89.8 20 96.5 98.0 95.9 96.6 24100.3 102.3 99.4 101.8

It is possible to point out that the release of the drug from theprepared systems is slowed down and the release of the whole drug takesapproximately 20 hours. In addition, it is clear that the releasekinetics are not substantially modified at any content level of activesubstance in the tablets. Such behaviour is in accordance with thepresent invention.

EXAMPLE 10 Systems Consisting of a Single Three-Layer Tablet—0.1 mg ofMoxonidina

In Example 10, the first layer consists of 100 mg of a “barrier” layer,the second layer (slow release) contains 0.1 mg of moxonidina; the thirdlayer consists of 100 mg of a “barrier” layer.

10(a) Preparation of the Granulate Utilised for the Preparation of theLayer Containing 0.1 mg of Slow Release Moxonidina.

Amount Component (mg) Moxonidina 0.10 mg Lactose monohydrate 29.90 mgHydroxypropylmethylcellulose (Methocel ® K 100 M, 50.00 mg Colorcon,Orpington, UK) (52 wt %) Glyceryl behenate (Compritol 888 Gattefossé,St. Priest; 10.00 mg F) Polyvinylpyrrolidone (Plasdone ® K29-32, I.S.P.)5.00 mg Magnesium stearate (USP grade, C. Erba, Milan, I) 1.00 mgColloidal silica (Syloid 244, Grace GmbH, Worms, D) 1.00 mg Total 97.00mg

In total, the active layer contains 56.7 weight % of gellable, swellableand/or erodible hydrophilic polymers (PVP+HPMC).

Mix moxonidina, lactose, hydroxypropylcellulose and glyceryl behenate,wet with a solution of 20% polyvinylpyrrolidone. Pass over a 25-meshsieve, desiccate in a fluid-bed desiccator (Aeromatic mod. Strea) untilconstant weight is reached, pass over the same mesh sieve again. Add thesilica and mix in a cubic mixer for 45 minutes, then add the magnesiumstearate and mix for a further 15 minutes. In this way a granulate(granulate 10(a)) is obtained with good slide and compaction properties.The granulate is subjected to the compression stage as described lateron.

10(b) Preparation of the Granulate Making Up the Barrier-Layers.

The composition and granulate described in Example 6(b) is utilised.

Component Amount Hydroxypropylmethylcellulose (Methocel ® K 100 M,39.88% Colorcon, Orpington, UK) Glyceryl behenate (Compritol 888Gattefossé, St. Priest; F) 13.50% Lactose monohydrate 39.88%Polyvinylpyrrolidone (Plasdone ® K29-32, I.S.P.) 5.00% Yellow iron oxideFCF (Sicovit Gelb 10-BASF Koln; D) 0.24% Magnesium stearate (USP grade,C. Erba, Milan, I) 1.00% Colloidal silica (Syloid 244, Grace GmbH,Worms, D) 0.50% Total 100.00%

Mix hydroxypropylmethylcellulose, glyceryl behenate and lactose andcarefully disperse the dye. Wet with a 5% an aqueous solution ofpolyvinylpyrrolidone. Pass over a 25-mesh sieve, desiccate in an oven(stove) at 30° C. for approximately 2 hours. Pass over the 25-mesh sieveagain. Desiccate until constant weight is reached. Add the colloidalsilica and magnesium stearate to the granulate obtained and mix inturbula for 15 minutes. In this way a granulate (granulate 10(b)) isobtained with good slide and compaction properties. The granulate issubjected to the compression stage as described later on.

10(c) Preparation of the Three-Layer Systems (by Compression).

The granulates obtained as previously quoted and according to well knownmodels to all experts in the field, are loaded in the feedboxes of arotary compressing machine suitable for producing three-layer tablets(e.g. Manesty Layer-Press LP 39, Liverpool, UK). In particular, thegranulate described in section 10(b) is loaded in the first and thirdfeedboxes; whereas the granulate as described in section 10(a) is loadedin the second feedbox. The compressing machine is equipped with 9 mmdiameter circular concave punches. The machine is set so as to producethree-layer systems consisting of an initial 100.00 mg of granulatebarrier, a second layer of 97.00 mg containing the active principle(equal to 0.10 mg of moxonidina.) and a third layer of 100.0 mg ofgranulate barrier. Working as previously described, three-layer tabletsare obtained with a mean weight of 297.00 mg, each containing 0.1 mg ofactive principle. Table 3 contains the data relating to the releaseverification of the active principle from the tablets in Example 10.

EXAMPLE 11 Systems Consisting of a Single Three-Layer Tablet—0.30 mgMoxonidina

In Example 11, the first layer consists of 100 mg of a “barrier” layer,the second layer (slow release) of 97.00 mg containing the activeprinciple (equal to 0.30 mg of moxonidina); the third layer consists of100 mg of a “barrier” layer.

11(a) Preparation of the Granulate Utilised for the Preparation of theLayer Containing 0.3 mg of Slow Release Moxonidina.

Amount Component (mg) Moxonidina 0.30 mg Lactose monohydrate 29.70 mg Hydroxypropylmethylcellulose (Methocel ® K 100 M, 50.00 mg  Colorcon,Orpington, UK) Glyceryl behenate (Compritol 888 Gattefossé, St. Priest;F) 10.00 mg  Polyvinylpyrrolidone (Plasdone ® K29-32, I.S.P.) 5.00 mgMagnesium stearate (USP grade, C. Erba, Milan, I) 1.00 mg Colloidalsilica (Syloid 244, Grace GmbH, Worms, D) 1.00 mg Total 97.00 mg 

A granulate is prepared as described in Example 10, in section 10(a),the only alteration being to triple the amount of carried activeprinciple; such a granulate makes up the second layer of the three-layertablet.

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example6 in section 6(b). The compressing machine is equipped with 9.0 mmdiameter circular concave punches. The machine is set so as to producethree-layer systems consisting of an initial 100.0 mg of granulatebarrier, a second layer of 97.00 mg containing the active principle(equal to 0.3 mg of moxonidina) and a third layer of 100.0 mg ofgranulate barrier. Working as previously described, three-layer tabletsare obtained with a mean weight of 297.00 mg, each containing 0.3 mg ofactive principle. Table 3 contains the data relating to the releaseverification of the active principle from the tablets in Example 11.

EXAMPLE 12 Systems Consisting of a Single Three-Layer Tablet—1.2 mgMoxonidina

In Example 12, the first layer consists of 100 mg of a “barrier” layer,the second layer (slow release) of contains 1.2 mg of moxonidina; thethird layer consists of 100 mg of a “barrier” layer.

12(a) Preparation of the Granulate Utilised for the Preparation of theLayer Containing 1.2 mg of Slow Release Moxonidina.

Amount Component (mg) Moxonidina 1.20 mg Lactose monohydrate 28.80 mgHydroxypropylmethylcellulose (Methocel ® K 100 M, 50.00 mg Colorcon,Orpington, UK) (52 wt %) Glyceryl behenate (Compritol 888 Gattefossé,St. Priest; 10.00 mg F) Polyvinylpyrrolidone (Plasdone ® K29-32, I.S.P.)5.00 mg Magnesium stearate (USP grade, C. Erba, Milan, I) 1.00 mgColloidal silica (Syloid 244, Grace GmbH, Worms, D) 1.00 mg Total 97.00mg

In total, the active layer contains 56.7 weight % of gellable, swellableand/or erodible hydrophilic polymers (PVP+HPMC).

A granulate is prepared as described in Example 11, in section 11(a),the only alteration being to quadruple the amount of carried activeprinciple, such a granulate makes up the second layer of the three-layertablet.

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example6 in section 6(b). The compressing machine is equipped with 9.0 mmdiameter circular concave punches. The machine is set so as to producethree-layer systems consisting of an initial 100.0 mg of granulatebarrier, a second layer of 97.00 mg containing the active principle(equal to 1.20 mg of moxonidina) and a third layer of 100.0 mg ofgranulate barrier. Working as previously described, three-layer tabletsare obtained with a mean weight of 297.00 mg, each containing 1.20 mg ofactive principle. Table 3 contains the data relating to the releaseverification of the active principle from the tablets in Example 12.

Dissolution Test of Tablets Prepared in Examples 10 to 12

To assess the release characteristics of the active principle from thethree-layer tablets, quoted in Examples 10-12, equipment 2 is utilised,paddle (USP XXIII), working at 100 r.p.m. and utilising as dissolutionfluid 900 mL of distilled water at 37° C. The release of the activeprinciple is followed by HPLC assessment at 230 nm utilising anautomatic Hewlett-Packard system with a diode array detector. Theresults of the experiments carried out are quoted in Table 3.

TABLE 3 TIME Percentage Released (hours) Example 10 Example 11 Example12 1 12.4 12.7 14.7 2 20.1 21.8 23.1 4 35.3 35.9 37.8 6 50.0 52.1 54.3 862.6 63.8 64.7 10 75.8 77.1 78.0 12 85.8 87.4 88.6 16 98.7 99.1 98.9 20100.3 101.2 99.4

It is possible to point out that the release of the drug from theprepared systems is slowed down and the release of the whole drug takesapproximately 20 hours. In addition, it is clear that the releasekinetics are not substantially modified, even if the active substancecontent in the tablets varies by 120%. Such behaviour is in accordancewith the present invention.

EXAMPLE 13 Systems Consisting of a Single Three-Layer Tablet—0.75 mgRopinirole

In Example 13, the first layer consists of 130 mg of a “barrier” layer,the second layer (slow release) contains 0.86 mg of Ropinirole HCl equalto 0.75 mg of base; the third layer consists of 120 mg of a “barrier”layer.

13(a) Preparation of the Granulate Utilised for the Preparation of theSlow Release Base Layer Containing 0.86 mg of Ropinirole HCl Equal to0.75 mg of Base

Component Amount (mg) Ropinirole HCl equal to 0.75 mg of base 0.86 mgHydroxypropylmethylcellulose (HPMC) (Methocel ® 61.50 mg K 100 M,Colorcon, Orpington, UK) (41 wt %) Sodium carboxymethylcellulose (NaCMC)(Blanose 15.00 mg 9 M31XF) (10 wt %) Maltodextrin NF (Lycatab DSH) 7.50mg (5 wt %) Lactose (C. Erba, Milan, I) 47.74 mg Hydrogenated castor oil(Cutina HR-Henkel, D) 15.00 mg (10 wt %) Magnesium stearate (C. Erba,Milan, I) 1.50 mg (1 wt %) Colloidal silica (Syloid 244, Grace GmbH,Worms, D) 0.90 mg Total 150.00 mg

In total, the active layer contains 51 weight % of the gellable,swellable and/or erodible hydrophilic polymers (HPMC+NaCMC), or 56 wt %if one includes maltodextrin.

Mix the Ropinirole and a part of the lactose for 20 minutes in asuitable mixer-granulator, (type Niro-Fielder PMA). Add thehydroxypropymethylcellulose, sodium carboxymethylcellulose, hydrogenatedcastor oil, maltodextrin and the remainder of the lactose and mix for 10minutes, wet with water (approx. 30% of the weight of the productsutilised). The granulate obtained is desiccated in a fluid-beddesiccator (type Niro-Fielder TSG 2) until constant weight is reached.Pass over an 0.800 mm mesh sieve oscillating granulator again. Add thesilica and mix in a cubic mixer for 20 minutes, then add the magnesiumstearate and mix for a further 10 minutes. In this way a granulate(granulate 13(a)) is obtained with good slide and compaction properties.The granulate is subjected to the compression stage as described lateron.

13(b) Preparation of the Granulate Making Up the Barrier-Layers.

Component Amount Hydroxypropylmethylcellulose (Methocel ® K  44.76% 100M, Colorcon, Orpington, UK) (or 44.75%) Mannitol (C. Erba)  23.60%Glyceryl behenate (Compritol 888 Gattefossé, St. Priest; F)  25.00%Polyvinylpyrrolidone (PVP) (Plasdone ® K29-32, I.S.P.)  5.00% Yellowiron oxide FCF (Sicovit Gelb 10-BASF Koln; D)  0.24% (or 0.25%)Magnesium stearate (USP grade, C. Erba, Milan, I)  1.00% Colloidalsilica (Syloid 244, Grace GmbH, Worms, D)  0.40% Total 100.00%

Mix hydroxypropylmethylcellulose, glyceryl behenate and mannitol andcarefully disperse the dye. Wet with a 5% aqueous solution ofpolyvinylpyrrolidone. Pass over a 25-mesh sieve, desiccate in an oven(stove) at 30° C. for approximately 2 hours. Pass over the 25-mesh sieveagain. Desiccate until constant weight is reached. Add the colloidalsilica and magnesium stearate to the granulate obtained and mix inturbula for 15 minutes. In this way a granulate (granulate 13(b)) isobtained with good slide and compaction properties. The granulate issubjected to the compression stage as described later on.

13(c) Preparation of the Three-Layer Systems (by Compression)

The granulates, obtained as previously quoted and according to wellknown models to all experts in the field, are loaded in the feedboxes ofa rotary compressing machine suitable for producing three-layer tablets(e.g. Manesty Layer-Press LP 39, Liverpool, UK). In particular, thegranulate described in section 13(b) is loaded in the first and thirdfeedboxes; whereas the granulate as described in section 13(a) is loadedin the second feedbox. The compressing machine is equipped with aslightly concave 9 mm diameter circular punches.

The machine is set so as to produce three-layer systems consisting of aninitial 130.0 mg of granulate barrier, a second layer of 150 mgcontaining the active principle (0.86 mg of Ropinirole HCl equal to 0.75mg of base) and a third layer of 120.0 mg of granulate barrier. Workingas previously described, three-layer tablets are obtained with a meanweight of 400.00 mg, each containing 0.86 mg of Ropinirole HCl, eachequal to 0.75 mg of base. Table 4 contains the data relating to therelease verification of the active principle from the tablets in Example13.

EXAMPLE 13A Variation of Example 13

In an alternative embodiment to Example 13, the preparation of thegranulate for the active layer 13(a) is done as follows:

-   -   Mix the HPMC, ropinirole, lactose, Na CMC, hydrogenated castor        oil and maltodextrin for 6 minutes in a suitable        mixer-granulator (type Niro Fielder PMA). Wet with water        (approx. 30% of the weight of the products utilised). The        granule obtained is desiccated in a fluid bed dryer (type Niro        Fielder TSG 2) until the water content is between 1 and 4.5%.        Pass through a 1.57 mm mesh sieve in a cone mill. Add silica and        mix in a cubic mixer for 20 minutes, then add the magnesium        stearate and mix for a further 2 minutes.

In this alternative embodiment, the preparation of the granulate for thebarrier layer 13(b) is done as follows:

-   -   Mix the mannitol, the dye, the glyceryl behenate, the HPMC, and        the PVP for 6 minutes in a suitable mixer-granulator (type Niro        Fielder PMA). Wet with water (approx. 25% of the weight of the        products utilised). The granule obtained is desiccated in a        fluid bed dryer (type Niro Fielder TSG 2) until water content is        between 1.1 and 2.7%. Pass through a 1.57 mm mesh sieve in a        cone mill. Add silica and mix in a cubic mixer for 20 minutes,        then add the magnesium stearate and mix for a further 2 minutes.

In further alternative embodiments, the above alternative procedures canalso be used, mutatis mutandis, with the ingredients/formulations of anyof the Examples 14 to 23 hereinafter.

EXAMPLE 14 Systems Consisting of a Single Three-Layer Tablet—1.00 mgRopinirole

In Example 14, the first layer consists of 130 mg of a “barrier” layer,the second layer (slow release) contains 1.14 mg of Ropinirole HCl equalto 1.00 mg of base; the third layer consists of 120 mg of a “barrier”layer.

A granulate is prepared as described in Example 13, in section 13(a),the only alteration being to increase the amount of carried activeprinciple, reducing the lactose content by the same amount; suchgranulate makes up the second layer of the three-layer tablet.

14(a) Preparation of the Granulate Utilised for the Preparation of theSlow Release Layer Containing 1.14 mg of Ropinirole HCl Equal to 1.00 mgof Base.

Component Amount (mg) Ropinirole HCl equal to 1.00 mg of base 1.14 mgHydroxypropylmethylcellulose (Methocel ® K 61.50 mg 100 M, Colorcon,Orpington, UK) Sodium carboxymethylcellulose (Blanose 9 15.00 mg M31XF)Maltodextrin NF (Lycatab DSH) 7.50 mg Lactose (C. Erba, Milan, I) 47.46mg Hydrogenated castor oil (Cutina HR-Henkel, D) 15.00 mg Magnesiumstearate (C. Erba, Milan, I) 1.50 mg Colloidal silica (Syloid 244, GraceGmbH, Worms, D) 0.90 mg Total 150.00 mg

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example13 in section 13(b). The compressing machine is equipped with slightlyconcave 9 mm diameter circular punches.

The machine is set so as to produce three-layer systems consisting of aninitial 130.0 mg of granulate barrier, a second layer of 150 mgcontaining 1.14 mg of Ropinirole HCl (equal to 1.00 mg of Ropinirolebase) and a third layer of 120.0 mg of granulate barrier. Working aspreviously described, three-layer tablets are obtained with a meanweight of 400.00 mg, each containing 1.14 mg of Ropinirole HCl, equal to1.00 mg of base. Table 4 contains the data relating to the releaseverification of the active principle from the tablets in Example 14.

EXAMPLE 15 Systems Consisting of a Single Three-Layer Tablet—3.00 mgRopinirole

In Example 15, the first layer consists of 130 mg of a “barrier” layer,the second layer (slow release) contains 3.42 mg of Ropinirole HCl equalto 3.00 mg of base; the third layer consists of 120 mg of “barrier”layer.

A granulate is prepared as described in Example 13, in section 13(a),the only alteration being to increase the amount of carried activeprinciple, reducing the lactose content by the same amount; suchgranulate makes up the second layer of the three-layer tablet.

15(a) Preparation of the Granulate Utilised for the Preparation of theSlow Release Layer Containing 3.42 mg of Ropinirole HCl Equal to 3.00 mgof Base

Component Amount (mg) Ropinirole HCl equal to 3.00 mg of base 3.42 mgHydroxypropylmethylcellulose (Methocel ® K 61.50 mg 100 M, Colorcon,Orpington, UK) Sodium carboxymethylcellulose (Blanose 9 M31XF) 15.00 mgMaltodextrin NF (Lycatab DSH) 7.50 mg Lactose (C. Erba, Milan, I) 45.18mg Hydrogenated castor oil (Cutina HR-Henkel, D) 15.00 mg Magnesiumstearate (C. Erba, Milan, I) 1.50 mg Colloidal silica (Syloid 244, GraceGmbH, Worms, D) 0.90 mg Total 150.00 mg

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example13 in section 13(b). The compressing machine is equipped with slightlyconcave 9 mm diameter circular punches.

The machine is set so as to produce three-layer systems consisting of aninitial 130.0 mg of granulate barrier, a second layer of 150 mgcontaining 3.42 mg of Ropinirole HCl (equal to 3.00 mg of Ropinirolebase) and a third layer of 120.0 mg of granulate barrier. Working aspreviously described, three-layer tablets are obtained with a meanweight of 400.00 mg, each containing 3.42 mg of Ropinirole HCl, eachequal to 3.00 mg of base. Table 4 contains the data relating to therelease verification of the active principle from the tablets in Example15.

EXAMPLE 16 Systems Consisting of a Single Three-Layer Tablet—6.00 mgRopinirole

In Example 16, the first layer consists of 130 mg of a “barrier” layer,the second layer (slow release) contains 6.84 mg of Ropinirole HCl equalto 6.00 mg of base; the third layer consists of 120 mg of a “barrier”layer.

A granulate is prepared as described in Example 13, in section 13(a),the only alteration being to increase the amount of carried activeprinciple, reducing the lactose content by the same amount; suchgranulate makes up the second layer of the three-layer tablet.

16(a) Preparation of the Granulate Utilised for the Preparation of theSlow Release Layer Containing 6.84 mg of Ropinirole HCl Equal to 6.00 mgof Base.

Component Amount (mg) Ropinirole HCl equal to 6.00 mg of base 6.84 mgHydroxypropylmethylcellulose (Methocel ® K 61.50 mg 100 M, Colorcon,Orpington, UK) Sodium carboxymethylcellulose (Blanose 9 M31XF) 15.00 mgMaltodextrin NF (Lycatab DSH) 7.50 mg Lactose (C. Erba, Milan, I) 41.76mg Hydrogenated castor oil (Cutina HR-Henkel, D) 15.00 mg Magnesiumstearate (C. Erba, Milan, I) 1.50 mg Colloidal silica (Syloid 244, GraceGmbH, Worms, D) 0.90 mg Total 150.00 mg

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example13 in section 13(b). The compressing machine is equipped with slightlyconcave 9 mm diameter circular punches. The machine is set so as toproduce three-layer systems consisting of an initial 130.0 mg ofgranulate barrier, a second layer of 150 mg containing 6.84 mg ofRopinirole HCl (equal to 6.00 mg of Ropinirole base) and a third layerof 120.0 mg of granulate barrier. Working as previously described,three-layer tablets are obtained with a mean weight of 400.00 mg, eachcontaining 6.84 mg of Ropinirole HCl, equal to 6.00 mg of base. Table 4contains the data relating to the release verification of the activeprinciple from the tablets in Example 16.

EXAMPLE 17 Systems Consisting of a Single Three-Layer Tablet—9.00 mgRopinirole

In Example 17, the first layer consists of 130 mg of a “barrier” layer,the second layer (slow release) contains 10.26 mg of Ropinirole HClequal to 9.00 mg of base; the third layer consists of 120 mg of a“barrier” layer.

A granulate is prepared as described in Example 13, in section 13(a),the only alteration being to increase the amount of carried activeprinciple, reducing the lactose content by the same amount; suchgranulate makes up the second layer of the three-layer tablet.

17(a) Preparation of the Granulate Utilised for the Preparation of theSlow Release Layer Containing 10.26 mg of Ropinirole HCl Equal to 9.00mg of Base

Component Amount (mg) Ropinirole HCl equal to 9.00 mg of base 10.26 mgHydroxypropylmethylcellulose (Methocel ® K 61.50 mg 100 M, Colorcon,Orpington, UK) Sodium carboxymethylcellulose (Blanose 9 M31XF) 15.00 mgMaltodextrin NF (Lycatab DSH) 7.50 mg Lactose (C. Erba, Milan, I) 38.34mg Hydrogenated castor oil (Cutina HR-Henkel, D) 15.00 mg Magnesiumstearate (C. Erba, Milan, I) 1.50 mg Colloidal silica (Syloid 244, GraceGmbH, Worms, D) 0.90 mg Total 150.00 mg

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example13 in section 13(b). The compressing machine is equipped with 8 mmdiameter circular concave punches. The machine is set so as to producethree-layer systems consisting of an initial 130.0 mg of granulatebarrier, a second layer of 150 mg containing the active principle (equalto 9.00 mg of Ropinirole base) and a third layer of 120.0 mg ofgranulate barrier. Working as previously described, three-layer tabletsare obtained with a mean weight of 400.00 mg, each containing 9.00 mg ofactive principle. Table 4 contains the data relating to the releaseverification of the active principle from the tablets in Example 17.

EXAMPLE 18 Systems Consisting of a Single Three-Layer Tablet—12.00 mgRopinirole

In Example 18, the first layer consists of 130 mg of a “barrier” layer,the second layer (slow release) contains 13.68 mg of Ropinirole HClequal to 12.00 mg of base; the third layer consists of 120 mg of a“barrier” layer.

A granulate is prepared as described in Example 13, in section 13(a),the only alteration being to increase the amount of carried activeprinciple, reducing the lactose content by the same amount; suchgranulate makes up the second layer of the three-layer tablet.

18(a) Preparation of the Granulate Utilised for the Preparation of theSlow Release Layer containing 13.68 mg of Ropinirole HCl Equal to 12.00mg of base.

Component Amount (mg) Ropinirole HCl equal to 12.00 mg of base 13.68 mgHydroxypropylmethylcellulose (Methocel ® K 61.50 mg 100 M, Colorcon,Orpington, UK) Sodium carboxymethylcellulose (Blanose 9 M31XF) 15.00 mgMaltodextrin NF (Lycatab DSH) 7.50 mg Lactose (C. Erba, Milan, I) 34.92mg Hydrogenated castor oil (Cutina HR-Henkel, D) 15.00 mg Magnesiumstearate (C. Erba, Milan, I) 1.50 mg Colloidal silica (Syloid 244, GraceGmbH, Worms, D) 0.90 mg Total 150.00 mg

For the first and third layer (barrier) a qualitatively andquantitatively identical granulate is employed, as described in Example13 in section 13(b). The compressing machine is equipped with 8 mmdiameter circular concave punches. The machine is set so as to producethree-layer systems consisting of an initial 130.0 mg of granulatebarrier, a second layer of 150 mg containing the active principle (equalto 12.00 mg of Ropinirole base) and a third layer of 120.0 mg ofgranulate barrier. Working as described previously, three-layer tabletsare obtained with a mean weight of 400.00 mg, each containing 12.00 mgof the active principle. Table 4 contains the data relating to therelease verification of the active principle from the tablets in Example18.

Dissolution Test of Tablets Prepared in Examples 13 to 18

To assess the release characteristics of the active principle from thethree-layer tablets, quoted in Examples 13-18, equipment 2 is utilised,paddle (USP XXIII), working at 100 r.p.m. and utilising as dissolutionfluid 500 mL of aqueous buffer solution of citrate (pH4.0), at 37° C.The release of the active principle is followed by HPLC assessment at250 nm utilising an automatic sampling and reading system. The resultsof the experiments carried out are quoted in Table 4.

TABLE 4 Percentage Released in Tablets of Examples 13 to 18 TIME (Ex. 13to Ex. 18) (hours) Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 Ex. 18 1 7.3 8.67.8 7.5 8.8 9.4 2 12.1 12.6 12.0 13.4 13.5 14.0 4 18.9 21.0 19.5 20.722.1 23.9 6 26.0 28.5 27.9 28.5 29.8 33.1 9 38.3 39.7 39.2 40.3 41.244.9 12 49.6 51.4 50.7 51.0 52.6 56.7 16 67.8 66.9 64.5 66.3 66.4 70.020 82.0 81.3 78.4 79.5 80.3 80.1 24 90.4 91.3 88.9 89.1 88.7 91.2

It is possible to point out that the release of the drug from theprepared systems is slowed down and the release of most of the drugtakes approximately 24 hours.

In addition, it is clear that the release kinetics are not substantiallymodified at any content of active substance in the tablets. Suchbehaviour is in accordance with the present invention.

EXAMPLE 19 Preparation of Ropinirole Round Tablet Formula

Tablet formulations of ropinirole as a round tablet were prepared asfollows. The tablet comprised an upper support or barrier layer (1), anactive layer (2) and a lower support or barrier layer (3). HPMC is anabbreviation for hydroxypropylmethylcellulose.

Support Layer (1)

Amount Component Role mg/tablet HPMC type 2208/K 100M Hydrophilic matrixpolymer 58.18 (100,000 cps) Mannitol Filler, Diluent 30.68 Glycerylbehenate Hydrophobic compound 32.50 Polyvinylpyrolidone (Povidone)Binder 6.50 Magnesium stearate Lubricant 1.30 Colloidal silicon dioxideGlidant 0.52 Yellow ferric oxide Colouring agent 0.33 Purified waterGranulation liquid b Total 130.00

Active Layer (2)

Described in terms of three tablet strength formulations of ropiniroleat 0.75 mg, 1 mg or 3 mg per tablet ropinirole measured as effectivebase present.

Amount mg/tablet Component Role 0.75 mg 1 mg 3 mg Ropinirole HCl ActiveSubstance 0.855 1.14 3.42 Lactose monohydrate Filler, diluent 47.74547.46 45.18 HPMC type 2208/K 100M Hydrophobic matrix 61.50 61.50 61.50(100,000 cps) polymer (41 wt %) Carboxymethylcellulose Viscosityregulating agent 15.00 15.00 15.00 sodium Maltodextrin Binder 7.50 7.507.50 Hydrogenated castor oil Hydrophobic compound 15.00 15.00 15.00Magnesium stearate Lubricant 1.50 1.50 1.50 olloidal silicon dioxideGlidant 0.90 0.90 0.90 Purified water Granulation liquid b b b Total150.00 150.00 150.00

Support Layer (3)

Amount Component Role mg/tablet HPMC type 2208/K 100M Hydrophilic matrixpolymer 53.70 (100,000 cps) Mannitol Filler, Diluent 28.32 Glycerylbehenate Hydrophobic compound 30.00 Polyvinylpyrolidone (Povidone)Binder 6.00 Magnesium stearate Lubricant 1.20 Colloidal silicon dioxideGlidant 0.48 Yellow ferric oxide Colouring agent 0.30 Purified waterGranulation liquid b Total 120.00

The purified water included as granulation liquid does not remain in thefinished product as indicated by the reference sign “b”.

EXAMPLE 20 Preparation of Ropinirole Caplet Formula

Tablet formulations of ropinirole as a caplet were prepared as follows.The tablet comprised an upper support or barrier layer (1), an activelayer (2) and a lower support or barrier layer (3), as shown in FIG. 9(in which reference numerals 10, 12 represent the barrier layers and 11the active layer). HPMC is an abbreviation forhydroxypropylmethylcellulose. Described in terms of four tablet strengthformulations of ropinirole at 1 mg, 3 mg, 6 mg, 9 mg or 12 mg per tabletropinirole measured as effective base present.

Support Layer (1)

Amount ropinirole (mg/tablet) Component Role 1 mg 3 mg 6 or 9 mg 12 mgHPMC type 2208 Hydrophilic matrix 76.07 76.07 76.07 76.07 (100,000 cps)polymer Mannitol Filler, diluent 40.12 40.12 40.12 40.12 Glycerylbehenate Hydrophobic compound 42.50 42.50 42.50 42.50Polyvinylpyrolidone Binder 8.50 8.50 8.50 8.50 (Povidone) Magnesiumstearate Lubricant 1.70 1.70 1.70 1.70 Colloidal silicon dioxide Glidant0.68 0.68 0.68 0.68 Yellow ferric oxide Colouring agent 0.43 0.43 0.430.43 Purified water Granulation liquid c c c c Total 170.00 170.00170.00 170.00

Active Layer (2)

Amount ropinirole (mg/tablet) Component Role 1 mg 3 mg 6 mg 9 mg 12 mgRopinirole HCl Active substance 1.14 3.42 6.84 10.26 13.68 Lactosemonohydrate Filler, diluent 47.46 45.18 41.76 38.34 34.92 HPMC type 2208Hydrophilic matrix 61.50 61.50 61.50 61.50 61.50 (100,000 cps) polymer(41 wt %) Carboxymethyl- Viscosity regulating 15.00 15.00 15.00 15.0015.00 cellulose sodium agent Maltodextrin Binder 7.50 7.50 7.50 7.507.50 Hydrogenated castor oil Hydrophobic 15.00 15.00 15.00 15.00 15.00compound Magnesium stearate Lubricant 1.50 1.50 1.50 1.50 1.50 Colloidalsilicon Glidant 0.90 0.900 0.90 0.90 0.90 dioxide Purified waterGranulation liquid c c c c c Total 150.00 150.00 150.00 150.00 150.00

Support Layer (3)

Amount ropinirole (mg/tablet) Component Role 1 mg 3 mg 6 or 9 mg 12 mgHPMC type 2208 Hydrophilic matrix 62.65 62.65 62.65 62.65 (100,000 cps)polymer Mannitol Filler, diluent 33.04 33.04 33.04 33.04 Glycerylbehenate Hydrophobic compound 35.00 35.00 35.00 35.00Polyvinylpyrolidone Binder 7.00 7.00 7.00 7.00 (Povidone) Magnesiumstearate Lubricant 1.40 1.40 1.40 1.40 Colloidal silicon dioxide Glidant0.56 0.56 0.56 0.56 Yellow ferric oxide Colouring agent 0.35 0.35 0.350.35 Purified water Granulation liquid c c c c Total 140.00 140.00140.00 140.00

Film Coating

Amount ropinirole (mg/tablet) Component Role 1 mg 3 mg 6 or 9 mg 12 mgOPADRY Coating 13.80 13.80 13.80 13.80 OY-S-28876 WHITE agent Purifiedwater Coating c c c c liquid Total tablet weight 473.80 473.80 473.80473.80 (layers 1, 2, 3 and coat)

The purified water included as granulation liquid or coating liquid doesnot remain in the finished product as indicated by the reference sign“c”. OPADRY OY-S-28876 WHITE is 63% BPMC 2910 6 cP, 7% PEG 400, 30%TiO2. Red/pink (0.01-0.25%) and/or yellow (0.1 to 1.5%) colourings canalso be added (iron oxides), the HPMC varying between 61-66%. Analternative blue coating uses 31-32% each of HPMC 2910 3 cP and HPMC2910 5 cP, 8% PEG400, 23-24% TiO2, 1% polysorbate, and indigotine asblue dye at 4-5%.

EXAMPLE 21 Preparation of Ropinirole Caplet Formula

Tablet formulations of ropinirole as a caplet were prepared as follows.The tablet comprised an upper support or barrier layer (1), an activelayer (2) and a lower support or barrier layer (3), as with example 20.Described in terms of four tablet strength formulations of ropinirole at1 mg, 3 mg, 6 mg, 9 mg and 12 mg per tablet ropinirole measured aseffective base present. This example is the same as Example 20 but theyellow ferric oxide in the support or barrier layers are absent.

Support Layer (1)

Amount ropinirole (mg/tablet) Component Role 1, 3 or 6 mg HPMC type 2208(100,000 cps) Hydrophilic matrix 76.50 polymer Mannitol Filler, diluent40.12 Glyceryl behenate Hydrophobic compound 42.50 Polyvinylpyrolidone(Povidone) Binder 8.50 Magnesium stearate Lubricant 1.70 Colloidalsilicon dioxide Glidant 0.68 Purified water Granulation liquid d Total170.00

Active Layer (2)

Amount ropinirole (mg/tablet) Component Role 1 mg 3 mg 6 mg 9 mg 12 mgRopinirole HCl Active substance 1.14 3.42 6.84 10.26 13.68 Lactosemonohydrate Filler, diluent 47.46 45.18 41.76 38.34 34.92 HPMC type 2208Hydrophilic matrix 61.50 61.50 61.50 61.50 61.50 (100,000 cps) polymer(41 wt %) Carboxymethyl- Viscosity regulating 15.00 15.00 15.00 15.0015.00 cellulose sodium agent Maltodextrin Binder 7.50 7.50 7.50 7.507.50 Hydrogenated castor oil Hydrophobic 15.00 15.00 15.00 15.00 15.00compound Magnesium stearate Lubricant 1.50 1.50 1.50 1.50 1.50 Colloidalsilicon Glidant 0.90 0.900 0.90 0.90 0.90 dioxide Purified waterGranulation liquid c c c c c Total 150.00 150.00 150.00 150.00 150.00

Support Layer (3)

Amount ropinirole (mg/tablet) Component Role 1, 3 or 6 mg HPMC type 2208(100,000 cps) Hydrophilic matrix 63.00 polymer Mannitol Filler, diluent33.04 Glyceryl behenate Hydrophobic compound 35.00 Polyvinylpyrolidone(Povidone) Binder 7.00 Magnesium stearate Lubricant 1.40 Colloidalsilicon dioxide Glidant 0.56 Purified water Granulation liquid d Total140.00

Film Coating

Amount ropinirole (mg/tablet) Component Role 1 mg 3 mg 6 or 9 mg 12 mgOPADRY Coating 13.80 13.80 13.80 13.80 OY-S-28876 WHITE agent Purifiedwater Coating d d d d liquid Total tablet weight 473.80 473.80 473.80473.80 (layers 1, 2, 3 and coat)

The purified water included as granulation liquid or coating liquid doesnot remain in the finished product as indicated by the reference sign“d”.

EXAMPLES 22 AND 23 Preparation of Ropinirole Caplet Formula

Tablet formulations of ropinirole as a caplet were prepared as follows.The tablet comprised an upper support or barrier layer (1), an activelayer (2) and a lower support or barrier layer (3), as for Examples 20and 21. Example formulations 22 and 23 are described as a single tabletstrength formulation each of ropinirole at 0.75 mg per tablet ropinirolemeasured as effective base present (0.855 mg measured as the HCl salt).As can be seen, Examples 22 and 23 involve identical active layers tothe 0.75 mg ropinirole active layer of Example 19, but different barrierlayers to Example 19, with different amounts and grades of HPMC in thebarrier layers, replacement of mannitol with lactose, and lower amountsof glyceryl behenate. As can be seen, Examples 22 and 23 have 10% and 40weight % respectively of K4M HPMC in their barrier layers which gives aslightly faster release profile in vitro than the ca. 45 wt % K100M HPMCpresent in the barrier layers of Examples 13-18 and 19-21, as inter aliathe ropinirole migrates faster through the barrier layers. Example 22has 20 wt % of K100LV HPMC as well as 10 wt % K4M HPMC in the barrierlayer—the low-viscosity (LV) HPMC in the barrier layer may increasewater uptake and aid gelling, increasing the matrix viscosity anddecreasing the release rate.

Support Layer (1) for Examples 22, 23

Amount (mg/tablet) Component Role Example 22 Example 23 HPMC K 4MHydrophilic matrix 13.00 51.84 polymer HPMC K100LV Hydrophilic matrix26.00 polymer Lactose monohydrate 64.68 51.84 Glyceryl behenateHydrophobic 17.56 17.55 compound Polyvinylpyrolidone Binder 6.50 6.50(Povidone) Magnesium stearate Lubricant 1.30 1.30 Colloidal siliconGlidant 0.64 0.63 dioxide Yellow ferric oxide Colouring agent 0.32 0.32Purified water Granulation liquid c c Total 130.00 130.00

Active Layer (2) for Examples 22 and 23

Described in terms of three tablet strength formulations of ropiniroleat 0.75 mg per tablet ropinirole measured as effective base present.

Amount ropinirole mg/tablet Component Role 0.75 mg Ropinirole HCl ActiveSubstance 0.855 Lactose monohydrate Filler, diluent 47.745 HPMC type2208/K Hydrophobic matrix 61.50 100M (100,000 cps) polymerCarboxymethylcellulose sodium Viscosity regulating agent 15.00Maltodextrin Binder 7.50 Hydrogenated castor oil Hydrophobic compound15.00 Magnesium stearate Lubricant 1.50 Colloidal silicon dioxideGlidant 0.90 Purified water Granulation liquid c Total 150.00

Support Layer (3) for Examples 22, 23

Amount (mg/tablet) Component Role Example 22 Example 23 HPMC K4MHydrophilic matrix 12.00 47.86 polymer HPMC K100LV 24.00 Lactosemonohydrate 59.70 47.86 Glyceryl behenate Hydrophobic 16.20 16.20compound Polyvinylpyrolidone Binder 6.00 6.00 (Povidone) Magnesiumstearate Lubricant 1.20 1.20 Colloidal silicon Glidant 0.60 0.60 dioxideYellow ferric oxide Colouring agent 0.30 0.30 Purified water Granulationliquid c c Total 120.00 120.00

The purified water included as granulation liquid or coating liquid doesnot remain in the finished product as indicated by the reference sign“c”.

Note: The active layer for each Example 22 and 23 above can be replacedby the active layers of examples 20 and 21 using 1 mg, 3 mg, 6 mg, 9 mgand 12 mg ropinirole measured as effective base present.

Note: in all the ropinirole examples 13-18 and 19-23, higher doses of upto 24 mg ropinirole per day can be administered by e.g. 2×12 mg tablets.Other doses e.g. 4 mg per day can be administered using 1×1 mg and 1×3mg tablet per day. Also, in any of the Examples 13-23, different dosesof for example 0.25 mg, 0.5 mg and 2 mg ropinirole can be used in theactive layer by varying the amount of lactose while keeping the totalweight of the active layer constant.

EXAMPLE 24 Further Studies on Caplet Preparation and Drug DissolutionProfiles

The following further studies on caplet preparation are presented toshow drug dissolution profiles for ropinirole caplets containing 0.75mg, 6 mg or 12 mg ropinirole measured as effective base present.

Formulation of Ropinirole HCl CR caplet, detailed per layer, mg/tabletIngredients Layer 1, support layer D14-4 Yellow HPMC type 2208 (100 000cps) 76.075 Mannitol 40.120 Glyceryl behenate 42.500 Povidone 8.500Yellow ferric oxide 0.425 Magnesium stearate vegetable 1.700 Colloidalsilicon dioxide 0.680 Purified water a Total 170.000 Layer 2, activelayer 0.75 mg 6 mg 12 mg Ropinirole HCl 0.855 6.840 13.680 Lactosemonohydrate 47.745 41.760 34.920 HPMC type 2208 (100 000 cps) 61.50061.500 61.500 Carboxymethlycellulose sodium 15.000 15.000 15.000Maltodextrin 7.500 7.500 7.500 Hydrogenated castor oil 15.000 15.00015.000 Magnesium stearate vegetable 1.500 1.500 1.500 Colloidal silicondioxide 0.900 0.900 0.900 Purified water a a a Total, layer 2 150.000150.000 150.000 Layer 3, support layer D14-4 Yellow HPMC type 2208 (100000 cps) 62.650 Mannitol 33.040 Glyceryl behenate 35.000 Povidone 7.000Yellow ferric oxide 0.350 Magnesium stearate vegetable 1.400 Colloidalsilicon dioxide 0.560 Purified water a Total 140.000 Film coating OPADRYOY-S-28876 WHITE 13.800 Purified water a Total, tablet 473.800 Notes: a= Does not remain in the final product 0.855 mg of Ropinirole HCl iscorresponding to 0.75 mg of Ropinirole Base 6.840 mg of Ropinirole HClis corresponding to 6.00 mg of Ropinirole Base 13.680 mg of RopiniroleHCl is corresponding to 12.00 mg of Ropinirole Base

The drug release profiles were measured using standard techniques. Theresults were as follows (results presented in terms of percentage drugreleased at given time intervals in hours):

Analytical results Dosage, mg 0.75 0.75 0.75 6 6 6 Batch no. C511 C519C529 C530 C531 C532 Tablet P00K41E P00K40E P00K39E P00K45E P00K46EP00K47E Tablet weight, mg 471.95 472.32 472.08 474.08 471.50 473.37Tablet wt RSD, % 0.78 1.44 0.65 0.98 1.10 1.08 Time, h 0.00 0.00 0.000.00 0.00 0.00 0.00 1.00 8.96 6.88 7.43 8.67 8.20 8.71 2.00 12.42 11.4511.69 13.47 13.17 13.48 4.00 19.99 19.93 19.59 22.03 22.01 21.55 6.0027.45 27.62 27.43 30.21 29.65 30.17 9.00 38.24 38.60 38.34 41.68 41.4641.81 12.00 49.78 49.58 50.00 52.07 52.36 52.33 16.00 64.53 64.48 65.4766.17 66.41 66.26 20.00 77.17 76.98 78.68 78.01 78.34 78.72 24.00 85.7986.17 88.18 87.09 87.69 88.19 30.00 92.40 93.57 95.40 95.26 94.81 95.4136.00 94.37 96.00 97.19 97.96 97.17 97.58 Dosage, mg 12 12 12 Batch no.C512 C534 C535 Tablet P00K42E P00K43E P00K44E Tablet weight, mg 470.39473.62 474.78 Tablet weight RSD, % 0.93 1.28 1.02 Time, h 0.00 0.00 0.000.00 1.00 9.45 10.10 9.73 2.00 14.87 15.53 15.23 4.00 24.37 24.87 24.556.00 33.38 33.74 33.33 9.00 45.56 46.22 45.81 12.00 56.81 57.40 56.7116.00 69.54 70.90 69.52 20.00 80.95 81.64 79.95 24.00 89.07 89.76 88.1230.00 95.76 96.63 94.60 36.00 97.80 99.38 97.26

1. A controlled release tablet comprising an amount of ropinirole,inclusive of pharmaceutically acceptable salts, which tablet exhibits arelease rate over approximately 24 hours in vitro as measured usingequipment 2, paddle (USP XXIII), working at 100 rpm and utilizing asdissolution fluid 500 ml of an aqueous buffer solution of citrate (pH4.0) at 37° C., and which tablet has an in vitro dissolution profile;wherein the release rate of ropinirole as a percentage is independent ofthe amount of ropinirole in said tablet, and wherein the tabletcomprises one active layer having a weight, said active layercontaining: (i) 0.75 mg to 12.0 mg ropinirole, inclusive ofpharmaceutically acceptable salts, measured as ropinirole base present;(ii) hydrophilic polymeric substances that gel and/or swell and/or erodeupon contact with aqueous liquids; (iii) lipophilic substances; and (iv)adjuvant substances; wherein the hydrophilic polymeric substances andthe lipophilic substances contained in said active layer, expressed as aweight ratio (w/w), ranges from 10:1 to 0.5:1.
 2. The controlled releasetablet according to claim 1, which has the in vitro dissolution profileshown in FIG.
 13. 3. The controlled release tablet according to claim 1or claim 2, which tablet is coated with a coating.
 4. The controlledrelease tablet according to claim 3, wherein the coating is a film ofgastroresistant and enterosoluble polymeric material.
 5. The controlledrelease tablet according to claim 1, which contains ropinirolehydrochloride.
 6. The controlled release tablet according to claim 1,wherein hydrophilic polymeric substances are present in a percentagebetween 30 and 75% of the weight of the active layer.
 7. The controlledrelease tablet according to claim 1, wherein the tablet is a multi-layertablet.